CALQUENCE Film-coated tablet Ref.[51594] Active ingredients: Acalabrutinib

Source: European Medicines Agency (EU)  Revision Year: 2023  Publisher: AstraZeneca AB, SE-151 85 Södertälje, Sweden

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors
ATC code: L01EL02

Mechanism of action

Acalabrutinib is a selective 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 with minimal off-target interactions.

Pharmacodynamic effects

In patients with B-cell malignancies dosed with acalabrutinib 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 46 healthy male and female subjects in a randomised, double-blind thorough QT study with placebo and positive controls. At a supratherapeutic dose, 4-times the maximum recommended dose, Calquence did not prolong the QT/QTc interval to any clinically relevant extent (e.g., not greater than or equal to 10 ms) (see sections 4.4, 4.8 and 5.3).

Clinical efficacy and safety

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, 27.9% patients had a CrCl of < 60 mL/min. Of the patients who were <65 years of age, 16.1% had a median CIRS-G score of 8. The study allowed patients to receive antithrombotic agents.

Patients who required anticoagulation with warfarin or equivalent vitamin K antagonists were excluded.

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 5 summarises the baseline demographics and disease characteristics of the study population.

Table 5. Baseline patient characteristics in (ELEVATE-TN) patients with previously untreated CLL:

Characteristic Calquence plus
obinutuzumab
N=179
Calquence
monotherapy
N=179
Obinutuzumab
plus
chlorambucil
N=177
Age, years; median (range) 70 (41-88) 70 (44-87) 71 (46-91)
Male; % 62 62 59.9
Caucasian; % 91.695 93.2
ECOG performance status 0-1; % 94.4 92.2 94.4
Median time from diagnosis (months) 30.5 24.4 30.7
Bulky disease with nodes ≥5 cm; % 25.7 38 31.1
Cytogenetics/FISH Category; %    
17p deletion 9.5 8.9 9
11q deletion 17.3 17.3 18.6
TP53 mutation 11.7 10.6 11.9
Unmutated IGHV 57.5 66.5 65.5
Complex karyotype (≥3 abnormalities) 16.2 17.3 18.1
Rai stage; %    
0 1.7 0 0.6
I 30.2 26.8 28.2
II 20.1 24.6 27.1
III 26.8 27.9 22.6
IV 21.2 20.7 21.5

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 treatmentrelated 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. Efficacy results are presented in Table 6.

Table 6. Efficacy results per IRC Assessments in (ELEVATE-TN) patients with CLL:

 Calquence plus
obinutuzumab
N=179
Calquence
monotherapy
N=179
Obinutuzumab
plus
chlorambucil
N=177
Progression-free survival*
Number of events (%) 14 (7.8) 26 (14.5) 93 (52.5)
PD, n (%) 9 (5) 20 (11.2) 82 (46.3)
Death events (%) 5 (2.8) 6 (3.4) 11 (6.2)
Median (95% CI), months NR NR (34.2, NR) 22.6 (20.2, 27.6)
HR (95% CI) 0.10 (0.06, 0.17) 0.20 (0.13, 0.30) -
P-value<0.0001<0.0001-
24 months estimate, %
(95% CI)
92.7 (87.4, 95.8) 87.3 (80.9, 91.7) 46.7 (38.5, 54.6)
Overall Survivala
Death events (%) 9 (5) 11 (6.1) 17 (9.6)
Hazard Ratio (95% CI) 0.47 (0.21, 1.06) 0.60 (0.28, 1.27) -
Best overall response rate* (CR + CRi + nPR + PR)
ORR, n (%)
(95% CI)
168 (93.9)
(89.3, 96.5)
153 (85.5)
(79.6, 89.9)
139 (78.5)
(71.9, 83.9)
P-value<0.0001 0.0763-
CR, n (%) 23 (12.8) 1 (0.6) 8 (4.5)
CRi, n (%) 1 (0.6) 0 0
nPR, n (%) 1 (0.6) 2 (1.1) 3 (1.7)
PR, n (%) 143 (79.9) 150 (83.8) 128 (72.3)

CI=confidence interval; HR=hazard ratio; NR=not reached; CR=complete response; CRi=complete response with incomplete blood count recovery; nPR=nodular partial response; PR=partial response.
* Per IRC assessment
Based on stratified Cox-Proportional-Hazards model
a Median OS not reached for both arms.

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 or 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.

Table 7. Subgroup analysis of PFS (Study ELEVATE-TN):

 Calquence monotherapy Calquence+G
N Hazard Ratio 95% CI N Hazard Ratio95% CI
All subjects 179 0.20(0.13, 0.30) 179 0.10(0.06, 0.17)
Del 17P
Yes
No
19
160
0.20
0.20

(0.12, 0.31)
21
158
0.13
0.09
(0.04, 0.46)
(0.05, 0.17)
TP53 mutation
Yes
No
19
160
0.15
0.20
(0.05, 0.46)
(0.12, 0.32)
21
158
0.04
0.11
(0.01, 0.22)
(0.06, 0.20)
Del 17P or/and TP53 mutation
Yes
No
23
156
0.23
0.19
(0.09, 0.61)
(0.11, 0.31)
25
154
0.10
0.10
(0.03, 0.34)
(0.05, 0.18)
IGHV mutation
Mutated
Unmutated
58
119
0.69
0.11
(0.31, 1.56)
(0.07, 0.19)
74
103
0.15
0.08
(0.04, 0.52)
(0.04, 0.16)
Del 11q
Yes
No
31
148
0.07
0.26
(0.02, 0.22)
(0.16, 0.41)
31
148
0.09
0.10
(0.03, 0.26)
(0.05, 0.20)
Complex Karyotype
Yes
No
31
117
0.10
0.27
(0.03, 0.33)
(0.16, 0.46)
29
126
0.09
0.11
(0.03, 0.29)
(0.05, 0.21)

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.

Table 8. Efficacy Results per INV assessment in (ELEVATE-TN) Patients with CLL:

 Calquence plus
obinutuzumab
N=179
Calquence
monotherapy
N=179
Obinutuzumab plus
Chlorambucil
N=177
Progression-free survival
Number of events (%) 27 (15.1) 50 (27.9) 124 (70.1)
PD, n (%) 14 (7.8) 30 (16.8) 112 (63.3)
Death events (%) 13 (7.3) 20 (11.2) 12 (6.8)
Median (95% CI),
months*
NR NR (66.5, NR) 27.8 (22.6, 33.2)
HR (95% CI) 0.11 (0.07, 0.16) 0.21 (0.15, 0.30) -
Overall survival
Death events (%) 18 (10.1) 30 (16.8) 28 (15.8)
Hazard Ratio
(95% CI)
0.55 (0.30, 0.99) 0.98 (0.58, 1.64) -

CI=confidence interval; HR=hazard ratio; NR=not reached
* 95% confidence interval based on Kaplan-Meier estimation.
Estimate based on stratified Cox-Proportional-Hazards model for Hazard Ratio (95% CI) stratified by 17p deletion status (yes vs no)

Figure 1. Kaplan-Meier Curve of INV-Assessed PFS in (ELEVATE-TN) Patients with CLL (ITT Population):

Month 0 3 6 9 1215 18 21 2427 30 33 36 394245 48 51 54 57 60 63 66 69 70
Calquence 179 167 163 158 156 155 153 150 149 146142 141 137 135 133 130 129 124 120 93 6339 2261
Calquence+G 179 175 170 168 164 163 160 157 156 156153 152 151 146144 141 140 13813399 65 39 27 7 1
GClb 177 163 156 153 139 125 110 100 86 82 67 66 56 49 44 40 38 31 30 20138720

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 not including BCL-2 inhibitors or B-cell receptor inhibitors. Patients received Calquence monotherapy or investigator’s choice of either idelalisib plus rituximab or bendamustine plus rituximab. The study allowed patients to receive antithrombotic agents. Patients who required anticoagulation with warfarin or equivalent vitamin K antagonists were excluded.

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 in combination with rituximab 375 mg/m² IV on Day 1 of the first cycle, followed by 500 mg/m² IV every 2 weeks for 4 doses, then every 4 weeks for 3 doses for a total of 8 infusions
    • 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.

Table 9. Baseline patient characteristics in (ASCEND) patients with CLL:

Characteristic Calquence
monotherapy
N=155
Investigator’s choice of
idelalisib + rituximab or
bendamustine +
rituximab
N=155
Age, years; median (range) 68 (32-89) 67 (34-90)
Male; % 69.7 64.5
Caucasian; % 93.5 91.0
ECOG performance status; %   
0 37.4 35.5
1 50.3 51.0
2 12.3 13.5
Median time from diagnosis (months) 85.3 79.0
Bulky disease with nodes ≥5 cm; % 49.0 48.4
Median number of prior CLL therapies (range) 1 (1-8) 2 (1-10)
Number of Prior CLL Therapies; %   
1 52.9 43.2
2 25.8 29.7
3 11.0 15.5
≥4 10.3 11.6
Cytogenetics/FISH Category; %   
17p deletion 18.1 13.5
11q deletion 25.2 28.4
TP53 mutation 25.2 21.9
Unmutated IGHV 76.1 80.6
Complex karyotype (≥3 abnormalities) 32.3 29.7
Rai Stage; %   
0 1.32.6
I 25.2 20.6
II 31.6 34.8
III 13.5 11.6
IV 28.4 29.7

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 16.1months, PFS indicated a 69% statistically significant reduction in the risk of death or progression for patients in the Calquence arm. Efficacy results are presented in Table 10. The Kaplan-Meier curve for PFS is shown in Figure 2.

Table 10. Efficacy results per IRC Assessments in (ASCEND) patients with CLL:

 Calquence monotherapy
N=155
Investigator’s choice of
idelalisib + rituximab or
bendamustine + rituximab
N=155
Progression-free survival*
Number of events (%) 27 (17.4) 68 (43.9)
PD, n (%) 19 (12.3) 59 (38.1)
Death events (%) 8 (5.2) 9 (5.8)
Median (95% CI), months NR 16.5 (14.0, 17.1)
HR (95% CI) 0.31 (0.20, 0.49)
P-value<0.0001
15 months estimate, % (95% CI) 82.6 (75.0, 88.1) 54.9 (45.4, 63.5)
Overall survivala
Death events (%) 15 (9.7) 18 (11.6)
Hazard Ratio (95% CI) 0.84 (0.42, 1.66) -
Best overall response rate* (CR + CRi + nPR + PR)**
ORR, n (%) (95% CI) 126 (81.3)
(74.4, 86.6)
117 (75.5)
(68.1, 81.6)
P-value 0.2248-
CR, n (%) 0 2 (1.3)
PR, n (%) 126 (81.3) 115 (74.2)
Duration of Response (DoR)
Median (95% CI), months NR 13.6 (11.9,NR)

CI=confidence interval; HR=hazard ratio; NR=not reached; CR=complete response; CRi=complete response with incomplete blood count recovery; nPR=nodular partial response; PR=partial response; PD=progressive disease
* Per IRC assessment
a Median OS not reached for both arms. P<0.6089 for OS.
** CRi and nPR have values of 0.
^† Based on stratified Cox-Proportional-Hazards model

Figure 2. Kaplan-Meier curve of IRC-assessed PFS in (ASCEND) patients with CLL (ITT Population):

Number of patients at risk
Month0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 161718 19 20 2122 23
Calquence 155 153 153 149 147 146 145 143 143 139139 137 118 116 73 61 60 25 21 21 1 1 1 0
Investigator’s
Choice
155 150 150 146 144 142 136 130 129 112105 101 82 77 56 44 39 18 10 8 0

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)].

Table 11. Subgroup analysis of IRC-assessed PFS (Study ASCEND):

 Calquence monotherapy
NHazard Ratio95% CI
All subjects 155 0.30(0.19, 0.48)
Del 17P
Yes
No
28
127
0.21
0.33
(0.07, 0.68)
(0.21, 0.54)
TP53 mutation
Yes
No
39
113
0.24
0.33
(0.11, 0.56)
(0.20, 0.57)
Del 17P or TP53 mutation
Yes
No
45
108
0.21
0.36
(0.09, 0.48)
(0.21, 0.61)
IGHV mutation
Mutated
Unmutated
33
118
0.32
0.32
(0.11, 0.94)
(0.19, 0.52)
Del 11q
Yes
No
39
116
0.28
0.31
(0.11, 0.70)
(0.19, 0.53)
Complex Karyotype
Yes
No
50
97
0.32
0.23
(0.16, 0.63)
(0.12, 0.44)

At final analysis, with a median follow-up of 46.5 months for Calquence and 45.3 months for the IR/BR, a 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. Efficacy results per Investigator Assessments (INV) are presented in Table 12. The Kaplan-Meier curve for INV assessed PFS is shown in Figure 3.

Table 12. Efficacy results at final analysis per INV assessments in (ASCEND) patients with CLL:

 Calquence monotherapy
N=155
Investigator’s choice of idelalisib +
rituximab or bendamustine +
rituximab
N=155
Progression-free survival*
Number of events (%) 62 (40.0) 119 (76.8)
PD, n (%) 43 (27.7) 102 (65.8)
Death events (%) 19 (12.3) 17 (11.0)
Median (95% CI), months NR 16.8 (14.1, 22.5)
HR (95% CI) 0.28 (0.20, 0.38)
Overall survivala
Death events (%) 41 (26.5) 54 (34.8)
Hazard Ratio (95% CI) 0.69 (0.46, 1.04) -

CI=confidence interval; HR=hazard ratio; NR=not reached; PD=progressive disease
* Per INV assessment
a Median OS not reached for both arms P=0.0783 for OS.
Based on stratified Cox-Proportional-Hazards model

Figure 3. Kaplan-Meier curve of INV-assessed PFS at final analysis in (ASCEND) patients with CLL:

Month 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54
Calquence 155 151 143 139 133 128 121 117 111 110 100 94 85 80 79 52 21 4 0
Investigator’s Choice 155 147 138 118 95 76 66 62 52 42 35 3228 2623125 0 

Investigator assessed PFS results at final analysis for Calquence were consistent across subgroups, including high risk features and were consistent with the primary analysis.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Calquence in all subsets of the paediatric population in CLL (for information on paediatric use, see section 4.2).

5.2. Pharmacokinetic properties

The pharmacokinetics (PK) of acalabrutinib and its active metabolite, ACP-5862, were studied in healthy subjects and in 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 is similar across patients with different Bcell malignancies. At the recommended dose of 100 mg twice daily in patients with B-cell malignancies (including, CLL), the geometric mean steady state daily area under the plasma concentration over time curve (AUC24h) and maximum plasma concentration (Cmax) for acalabrutinib were 1679 ng•h/mL and 438 ng/mL, respectively, and for ACP-5862 were 4166 ng•h/mL and 446 ng/mL, respectively.

Calquence tablets and Calquence capsules have been demonstrated to be bioequivalent. Calquence tablets contain acalabrutinib maleate, a salt form of acalabrutinib that shows higher solubility at high pH than the acalabrutinib base, which is the active content of Calquence capsules. Calquence tablets thus have a better absorption when combined with acid reducing agents.

Absorption

The time to peak plasma concentrations (Tmax) was 0.2-3.0 hours for acalabrutinib, and 0.5-4.0 hours for ACP-5862. The absolute bioavailability of Calquence was 25%.

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.

Distribution

Reversible binding to human plasma protein was 99.4% for acalabrutinib and 98.8% 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.

Biotransformation/Metabolism

In vitro, acalabrutinib is predominantly metabolised by CYP3A enzymes, and to a minor extent by glutathione conjugation and amide hydrolysis. ACP-5862 was identified as the major metabolite in plasma, that was further metabolized primarily by CYP3A-mediated oxidation, 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 studies indicate that acalabrutinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, UGT1A1 or UGT2B7 at clinically relevant concentrations and is unlikely to affect clearance of substrates of these CYPs.

In vitro studies indicate that ACP-5862 does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, UGT1A1 or UGT2B7 at clinically relevant concentrations and is unlikely to affect clearance of substrates of these CYPs.

Interactions with transport proteins

In vitro studies indicate that acalabrutinib and ACP-5862 are P-gp and BCRP substrates. Coadministration with BCRP inhibitors is however unlikely to result in clinically relevant drug interactions. Co-administration with an OATP1B1/1B3 inhibitor (600 mg rifampin, single dose) resulted in an increase in acalabrutinib Cmax and AUC by 1.2-fold and 1.4-fold (N=24, healthy subjects), respectively, which is not clinically relevant.

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, while ACP5862 may inhibit MATE1 at clinically relevant concentrations (see section 4.5). 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 tablet, the geometric mean terminal elimination halflife (t1/2) of acalabrutinib was 1.4 hours. The t1/2 of the active metabolite, ACP-5862, was 6.6 hours.

The mean apparent oral clearance (CL/F) was 134 L/hr for acalabrutinib and 22 L/hr for ACP-5862 in patients with B-cell malignancies.

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.

Special populations

Based on population PK analysis, age (>18 years of 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.

Paediatric population

No pharmacokinetic studies were performed with Calquence in patients under 18 years of age.

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 408 subjects with mild renal impairment (eGFR between 60 and 89 mL/min/1.73m² as estimated by MDRD), 109 subjects with moderate renal impairment (eGFR between 30 and 59 mL/min/1.73m²) relative to 192 subjects 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 studies (see section 4.2).

Hepatic impairment

Acalabrutinib is metabolised in the liver. In dedicated hepatic impairment (HI) 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. Subjects in the moderate HI group were however not significantly affected in markers relevant for the elimination capacity of drugs, so the effect of moderate hepatic impairment was likely underestimated in this study. 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=613) hepatic function (total bilirubin and AST within ULN) (see section 4.2).

5.3. Preclinical safety data

Carcinogenicity

Carcinogenicity studies have not been conducted with acalabrutinib.

Genotoxicity/Mutagenicity/Phototoxicity

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.

Based on phototoxicity assays using 3T3 cell line in vitro, acalabrutinib is considered to have a low risk for phototoxicity in humans.

Repeat-dose toxicity

In rats, microscopic findings of minimal to mild severity were observed in the pancreas (haemorrhage/pigment/inflammation/fibrosis in islets) at all dose levels. Non-adverse findings of minimal to mild severity in the kidneys (tubular basophilia, tubular regeneration, and inflammation) were observed in studies of up to 6-month duration with a No Observed Adverse Effect level (NOAEL) of 30 mg/kg/day in rats. The mean exposures (AUC) at the NOAEL in male and female rats correspond to 0.6x and 1x, respectively, the clinical exposure at the recommended dose of 100 mg twice daily, respectively. The Lowest Adverse Observed Effect Level (LOAEL) at which reversible renal (moderate tubular degeneration) and liver (individual hepatocyte necrosis) findings were observed in the chronic rat study was 100 mg/kg/day and provided an exposure margin 4.2-times greater than the clinical exposure at the recommended dose of 100 mg twice daily. In studies of 9 months duration in dogs, the NOAEL was 10 mg/kg/day corresponding to an exposure 3-times the clinical AUC at the recommended clinical dose. Minimal tubular degeneration in kidney, slight decreases in spleen weights and transient minimal to mild decreases in red cell mass and increases in ALT and ALP were observed at 30 mg/kg/day (9-times the clinical AUC) in dogs. Cardiac toxicities in rats (myocardial haemorrhage, inflammation, necrosis) and dogs (perivascular/vascular inflammation) were observed only in animals that died during studies at doses above the maximum tolerated dose (MTD). The exposures in rats and dogs with cardiac findings was at least 6.8-times and 25-times the clinical AUC, respectively. Reversibility for the heart findings could not be assessed as these findings were only observed at doses above the MTD.

Reproductive toxicology

No effects on fertility were observed in male or female rats at exposures 10- or 9-times the clinical AUC at the recommended dose, respectively.

No effects on embryofoetal development and survival were observed in pregnant rats, at exposures approximately 9-times the AUC in patients at the recommended dose of 100 mg twice daily. In two rat reproductive studies, dystocia (prolonged/difficult labour) was observed at exposures >2.3-times the clinical exposure at 100 mg twice daily. The presence of acalabrutinib and its active metabolite were confirmed in foetal rat plasma. Acalabrutinib and its active metabolite were present in the milk of lactating rats.

In an embryofoetal study in pregnant rabbits, decreased foetal body weight and delayed ossification were observed at exposure levels that produced maternal toxicity which were 2.4-times greater than the human AUC at the recommended dose.

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