CALQUENCE 100mg capsules medication leaflet

Calquence 100 mg hard capsules

Each hard capsule contains 100 mg of acalabrutinib.

For the full list of excipients, see section 6.1.

Hard capsule (capsule).

Yellow body, blue cap, size 1 (20 mm) hard capsule, marked with “ACA 100 mg” in black ink.

Calquence as monotherapy or in combination with obinutuzumab is indicated for the treatment of adultpatients with previously untreated chronic lymphocytic leukaemia (CLL).

Calquence as monotherapy is indicated for the treatment of adult patients with chronic lymphocyticleukaemia (CLL) who have received at least one prior therapy.

Calquence in combination with bendamustine and rituximab (BR) is indicated for the treatment of adultpatients with previously untreated mantle cell lymphoma (MCL) who are not eligible for autologous stemcell transplant (ASCT).

Calquence as monotherapy is indicated for the treatment of adult patients with relapsed or refractorymantle cell lymphoma (MCL) not previously treated with a BTK inhibitor.

Treatment with this medicinal product should be initiated and supervised by a physician experienced inthe use of anticancer medicinal products.

The recommended dose of Calquence in monotherapy or in combination with other medicinal products is100 mg acalabrutinib twice daily (equivalent to a total daily dose of 200 mg).

The dose interval is approximately 12 hours.

Treatment with Calquence should be continued until disease progression or unacceptable toxicity.

For the combination regimens, refer to the prescribing information of each of the medicinal product fortheir dosing information (for details of the combination regimens, see section 5.1).

Calquence in combination with bendamustine and rituximab

Calquence should be administered on Day 1 on Cycle 1 (each cycle is 28 days) until disease progressionor unacceptable toxicity. Bendamustine should be administered at 90 mg/m2 on Days 1 and 2 of eachcycle for a total of 6 cycles. Rituximab should be administered at 375 mg/m2 on Day 1 each cycle for atotal of 6 cycles. Patients achieving a response (partial response [PR] or complete response [CR]) after thefirst 6 cycles, may receive maintenance rituximab at 375 mg/m2 on Day 1 of every other cycle for amaximum of 12 additional doses, starting on Cycle 8 up to Cycle 30.

Adverse reactions

Recommended dose modifications of Calquence for Grade ≥ 3 adverse reactions in patients receiving

Calquence monotherapy and Calquence in combination with obinutuzumab are provided in Table 1.

Recommended dose modifications for Grade ≥ 3 adverse reactions in patients receiving Calquence incombination with bendamustine and rituximab are provided in Table 2.

Table 1. Recommended dose adjustments for adverse reactions*

Adverse reaction Adverse Dose modificationreaction (Starting dose = 100mg approximately every 12occurrence hours)

Grade 3 thrombocytopenia First and second Interrupt Calquencewith bleeding, Once toxicity has resolved to Grade 1 or

Grade 4 thrombocytopenia baseline, Calquence may be resumed at 100mg

Or approximately every 12 hours

Grade 4 neutropenia lasting Third Interrupt Calquencelonger than 7 days Once toxicity has resolved to Grade 1 orbaseline, Calquence may be resumed at a reduced

Grade 3 or greater non- frequency of 100mg once dailyhaematological toxicities Fourth Discontinue Calquence

*Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI

CTCAE) version 4.03.

Table 2. Recommended dose adjustments for Grade ≥ 3 adverse reactions* in patients receiving

Calquence in combination with bendamustine and rituximab

Adverse reaction Bendamustine dose Calquence dose modificationmodification†

Neutropenia If Grade 3 or Grade 4 If Grade 4 neutropenia lasting longer than 7neutropenia‡: days then interrupt Calquence.

Interrupt bendamustine. Once toxicity has resolved to Grade ≤ 2 or

Once toxicity has resolved baseline level, Calquence may be resumedto Grade ≤ 2 or baseline at starting dose (1st adverse reactionlevel, bendamustine may occurrence) or at a reduced frequency ofbe resumed at 70 mg/m2. 100 mg once daily (2nd and 3rd adverse

Discontinue bendamustine reaction occurrence).¶if additional dose Discontinue Calquence at 4th adversereduction is required. reaction occurrence.

Thrombocytopenia If Grade 3 or Grade 4 If Grade 3 thrombocytopenia withthrombocytopenia: significant bleeding or Grade 4 then

Interrupt bendamustine. interrupt Calquence.

Once toxicity has resolved Once toxicity has resolved to Grade ≤ 2 orto Grade ≤ 2 or baseline baseline level, Calquence may be resumedlevel, bendamustine may at starting dose (1st adverse reactionbe resumed at 70 mg/m2. occurrence) or at a reduced frequency of

Discontinue bendamustine 100 mg once daily (2nd and 3rd occurrence).¶if additional dose Discontinue Calquence at 3rd adversereduction is required. reaction occurrence for thrombocytopeniawith significant bleeding.

Discontinue Calquence at 4th adversereaction occurrence.

Other hematologic Interrupt bendamustine. Interrupt Calquence.

Grade 4§ or Once toxicity has resolved Once toxicity has resolved to Grade ≤ 2 orunmanageable Grade 3 to Grade ≤ 2 or baseline baseline level, Calquence may be resumedtoxicity level, bendamustine may at starting dose (1st adverse reactionbe resumed at 70 mg/m2. occurrence) or at a reduced frequency of

Discontinue bendamustine 100 mg once daily (2nd and 3rd adverseif additional dose reaction occurrence).¶reduction is required. Discontinue Calquence at 4th adversereaction occurrence.

Grade 3 or greater Interrupt bendamustine. Interrupt Calquence.

non-hematologic Once toxicity has resolved Once toxicity has resolved to Grade 2 ortoxicities to Grade 1 or baseline baseline, Calquence may be resumed atlevel, bendamustine may starting dose (1st adverse reactionbe resumed at 70 mg/m2. occurrence) or at a reduced frequency of

Discontinue bendamustine 100 mg once daily (2nd adverse reactionif additional dose occurrence).¶reduction is required. Discontinue Calquence at 3rd adversereaction occurrence.

*Adverse reactions graded by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI

CTCAE) version 4.03.†For any toxicities not listed in this table refer to the bendamustine local prescribing information.‡Consider use of myeloid growth factors before bendamustine dose modifications.§Grade 4 lymphopenia is an expected outcome for treatment with bendamustine and rituximab. Dose modificationdue to lymphopenia is expected only if considered clinically important by investigators e.g. associated recurrentinfections.¶Dose may be re-escalated at the discretion of the physician if patient tolerates a reduced dose for ≥4 weeks.

Refer to the prescribing information of each of the medicinal products used in combination with

Calquence for additional information for management of toxicities.

Recommendations regarding use of Calquence with CYP3A inhibitors or inducers and gastric acidreducing agents are provided in Table 3 (see section 4.5).

Table 3. Use with CYP3A inhibitors or inducers and gastric acid reducing agents

Co-administered

Recommended Calquence usemedicinal product

Avoid concomitant use.

Strong CYP3A inhibitor If these inhibitors will be used short-term (such asanti-infectives for up to seven days), interrupt Calquence.

CYP3Ainhibitors

Moderate CYP3A No dose adjustment. Monitor patients closely for adverseinhibitor reactions if taking moderate CYP3A inhibitors.

Mild CYP3A inhibitor No dose adjustment.

CYP3A

Strong CYP3A inducer Avoid concomitant use.

inducers

Proton pump inhibitors Avoid concomitant use.

Gastric

Take Calquence 2 hours before (or 10 hours after) takingacid H2-receptor antagonistsa H2-receptor antagonist.

reducingagents The interval between taking the medicinal products

Antacidsshould be at least 2 hours.

If a patient misses a dose of Calquence by more than 3 hours, the patient should be instructed to take thenext dose at its regularly scheduled time. Double dose of Calquence should not be taken to make up for amissed dose.

No dose adjustment is required for elderly patients (aged ≥ 65 years) (see section 5.2).

No specific clinical studies have been conducted in patients with renal impairment. Patients with mild ormoderate renal impairment were treated in Calquence clinical studies. No dose adjustment is needed forpatients with mild or moderate renal impairment (greater than 30 mL/min creatinine clearance). Hydrationshould be maintained, and serum creatinine levels monitored periodically. Calquence should beadministered to patients with severe renal impairment (< 30mL/min creatinine clearance) only if thebenefit outweighs the risk and these patients should be monitored closely for signs of toxicity. There areno data in patients with severe renal impairment or patients on dialysis (see section 5.2).

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).

However, patients with moderate hepatic impairment should be closely monitored for signs of toxicity. Itis not recommended to use Calquence in patients with severe hepatic impairment (Child-Pugh C or totalbilirubin >3-times ULN and any AST) (see section 5.2).

Severe cardiac disease

Patients with severe cardiovascular disease were excluded from Calquence clinical studies.

The safety and efficacy of Calquence in children and adolescents aged 0 to 18 years have not beenestablished. No data are available.

Calquence is for oral use. The capsules should be swallowed whole with water at approximately the sametime each day, with or without food (see section 4.5). The capsules should not be chewed, dissolved oropened as this may affect the absorption of the medicinal product into the body.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Major haemorrhagic events including central nervous system and gastrointestinal haemorrhage, some withfatal outcome, have occurred in patients with haematologic malignancies treated with Calquencemonotherapy and in combination with other medicinal products. These events have occurred in patientsboth with and without thrombocytopenia. Overall, the bleeding events were less severe events includingbruising and petechiae (see section 4.8).

The mechanism for the bleeding events is not well understood.

Patients receiving antithrombotic agents may be at increased risk of haemorrhage. Use caution withantithrombotic agents and consider additional monitoring for signs of bleeding when concomitant use ismedically necessary. Warfarin or other vitamin K antagonists should not be administered concomitantlywith Calquence.

Consider the benefit-risk of withholding Calquence for at least 3 days pre- and post-surgery.

Serious infections (bacterial, viral or fungal), including fatal events have occurred in patients withhaematologic malignancies treated with Calquence monotherapy and in combination with other medicinalproducts. These infections predominantly occurred in the absence of neutropenia, with neutropenicinfection reported in 10.1% of patients receiving monotherapy and 23.9% in patients receivingcombination therapy. Infections due to hepatitis B virus (HBV) and herpes zoster virus (HZV)reactivation, aspergillosis and progressive multifocal leukoencephalopathy (PML) have occurred (seesection 4.8).

Cases of hepatitis B reactivation have been reported in patients receiving Calquence. Hepatitis B virus(HBV) status should be established before initiating treatment with Calquence. If patients have positivehepatitis B serology, a liver disease expert should be consulted before the start of treatment and the patientshould be monitored and managed following local medical standards to prevent hepatitis B reactivation.

Cases of progressive multifocal leukoencephalopathy (PML) including fatal ones have been reportedfollowing the use of Calquence within the context of a prior or concomitant immunosuppressive therapy.

Physicians should consider PML in the differential diagnosis in patients with new or worseningneurological, cognitive or behavioural signs or symptoms. If PML is suspected, then appropriatediagnostic evaluations should be undertaken and treatment with Calquence should be suspended until

PML is excluded. If any doubt exists, referral to a neurologist and appropriate diagnostic measures for

PML including MRI scan preferably with contrast, cerebrospinal fluid (CSF) testing for JC Viral DNAand repeat neurological assessments should be considered.

Consider prophylaxis according to standard of care in patients who are at increased risk for opportunisticinfections. Monitor patients for signs and symptoms of infection and treat as medically appropriate.

Cytopenias

Treatment-emergent Grade 3 or 4 cytopenias, including neutropenia, anaemia and thrombocytopenia,occurred in patients with haematologic malignancies treated with Calquence monotherapy and incombination with other medicinal products. Monitor complete blood counts as medically indicated (seesection 4.8).

Second primary malignancies

Second primary malignancies, including skin and non-skin cancers, occurred in patients withhaematologic malignancies treated with Calquence monotherapy and in combination with other medicinalproducts. Skin cancers were commonly reported. Monitor patients for the appearance of skin cancers andadvise protection from sun exposure (see section 4.8).

Atrial fibrillation

Atrial fibrillation/flutter occurred in patients with haematologic malignancies treated with Calquencemonotherapy and in combination with other medicinal products. Monitor for symptoms (e.g., palpitations,dizziness, syncope, chest pain, dyspnoea) of atrial fibrillation and atrial flutter and obtain an ECG asmedically indicated (see sections 4.5 and 4.2). In patients who develop atrial fibrillation on therapy with

Calquence, a thorough assessment of the risk for thromboembolic disease should be undertaken. Inpatients at high risk for thromboembolic disease, tightly controlled treatment with anticoagulants andalternative treatment options to Calquence should be considered.

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 closelymonitored as clinically indicated.

Interstitial lung disease/pneumonitis

Interstitial lung disease (ILD)/pneumonitis has been reported in patients treated with Calquence incombination with bendamustine and rituximab in MCL. Monitor patients for pulmonary symptomsindicative of ILD/pneumonitis (e.g. cough, dyspnea or hypoxia) and manage ILD/pneumonitis asclinically indicated.

Other medicinal products

Co-administration of strong CYP3A inhibitors with Calquence may lead to increased acalabrutinibexposure and consequently a higher risk for toxicity. On the contrary, co-administration of CYP3Ainducers may lead to decreased acalabrutinib exposure and consequently a risk for lack of efficacy.

Concomitant use with strong CYP3A inhibitors should be avoided. If these inhibitors will be used short-term (such as anti-infectives for up to seven days), treatment with Calquence should be interrupted.

Patients should be closely monitored for signs of toxicity if a moderate CYP3A inhibitor is used (seesections 4.2 and 4.5). Concomitant use with strong CYP3A4 inducers should be avoided due to risk forlack of efficacy.

Calquence contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

Acalabrutinib and its active metabolite are primarily metabolised by cytochrome P450 enzyme 3A4(CYP3A4), and both substances are substrates for P-gp and breast cancer resistance protein (BCRP).

Active substances that may increase acalabrutinib plasma concentrations

CYP3A/P-gp inhibitors

Co-administration with a strong CYP3A/P-gp inhibitor (200 mg itraconazole once daily for 5 days)increased acalabrutinib Cmax and AUC by 3.9-fold and 5.0-fold in healthy subjects (N=17), respectively.

Concomitant use with strong CYP3A/P-gp inhibitors should be avoided. If the strong CYP3A/P-gpinhibitors (e.g., ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole, ritonavir, telaprevir,posaconazole, voriconazole) will be used short-term, treatment with Calquence should be interrupted (seesection 4.2).

Co-administration with moderate CYP3A inhibitors (400 mg fluconazole as single dose or 200 mgisavuconazole as repeated dose for 5 days) in healthy subjects increased acalabrutinib Cmax and AUC by1.4-fold to 2-fold while the active metabolite ACP-5862 Cmax and AUC was decreased by 0.65-fold to0.88-fold relative to when acalabrutinib was dosed alone. No dose adjustment is required in combinationwith moderate CYP3A inhibitors. Monitor patients closely for adverse reactions (see Section 4.2).

Active substances that may decrease acalabrutinib plasma concentrations

Co-administration of a strong CYP3A inducer (600 mg rifampicin once daily for 9 days) decreasedacalabrutinib Cmax and AUC by 68% and 77% in healthy subjects (N=24), respectively.

Concomitant use with strong inducers of CYP3A activity (e.g., phenytoin, rifampicin, carbamazepine)should be avoided. Concomitant treatment with St. John’s wort, which may unpredictably decreaseacalabrutinib plasma concentrations, should be avoided.

Gastric acid reducing medicinal products

Acalabrutinib solubility decreases with increasing pH. Co-administration of acalabrutinib with an antacid(1 g calcium carbonate) decreased acalabrutinib AUC by 53% in healthy subjects. Co-administration witha proton pump inhibitor (40 mg omeprazole for 5 days) decreased acalabrutinib AUC by 43%.

If treatment with an acid reducing agent is required, consider using an antacid (e.g., calcium carbonate), oran H2-receptor antagonist (e.g., ranitidine or famotidine). For use with antacids, the interval betweentaking the medicinal products should be at least 2 hours (see section 4.2). For H2-receptor antagonists,

Calquence should be taken 2 hours before (or 10 hours after) taking the H2-receptor antagonist.

Due to the long-lasting effect of proton pump inhibitors, separation of doses with proton pump inhibitorsmay not eliminate the interaction with Calquence and therefore concomitant use should be avoided (seesection 4.2).

Active substances whose plasma concentrations may be altered by Calquence

Based on in vitro data, it cannot be excluded that acalabrutinib is an inhibitor of CYP3A4 at the intestinallevel and may increase the exposure of CYP3A4 substrates sensitive to gut CYP3A metabolism. Cautionshould be exercised if co-administering acalabrutinib with CYP3A4 substrates with narrow therapeuticrange administered orally (e.g., cyclosporine, ergotamine, pimozide).

Effect of acalabrutinib on CYP1A2 substrates

In vitro studies indicate that acalabrutinib induces CYP1A2. Co-administration of acalabrutinib with

CYP1A2 substrates (e.g., theophylline, caffeine) may decrease their exposure.

Effects of acalabrutinib and its active metabolite, ACP-5862, on medicinal product transport systems

Acalabrutinib may increase exposure to co-administered BCRP substrates (e.g., methotrexate) byinhibition of intestinal BCRP (see section 5.2). To minimise the potential for an interaction in the

Gastrointestinal (GI) tract, oral narrow therapeutic range BCRP substrates such as methotrexate should betaken at least 6 hours before or after acalabrutinib.

ACP-5862 may increase exposure to co-administered MATE1 substrates (e.g., metformin) by inhibition of

MATE1 (see section 5.2). Patients taking concomitant medicinal products with disposition dependentupon MATE1 (e.g., metformin) should be monitored for signs of changed tolerability as a result ofincreased exposure of the concomitant medication whilst receiving Calquence.

Women of childbearing potential should be advised to avoid becoming pregnant while receiving

Calquence.

There are no or limited amount of data from the use of acalabrutinib in pregnant women. Based onfindings from animal studies, there may be a risk to the foetus from exposure to acalabrutinib duringpregnancy. Dystocia (difficult or prolonged labour) was observed in the rat and administration to pregnantrabbits was associated with reduced foetal growth (see section 5.3).

Calquence should not be used during pregnancy unless the clinical condition of the woman requirestreatment with acalabrutinib.

It is not known whether acalabrutinib is excreted in human milk. There are no data on the effect ofacalabrutinib on the breast-fed child or on milk production. Acalabrutinib and its active metabolite werepresent in the milk of lactating rats. A risk to the breast-fed child cannot be excluded. Breast-feedingmothers are advised not to breast-feed during treatment with Calquence and for 2 days after receiving thelast dose.

There are no data on the effect of Calquence on human fertility. In a non-clinical study of acalabrutinib inmale and female rats, no adverse effects on fertility parameters were observed (see section 5.3).

Calquence has no or negligible influence on the ability to drive and use machines. However, duringtreatment with acalabrutinib, fatigue and dizziness have been reported and patients who experience thesesymptoms should be advised not to drive or use machines until symptoms abate.

Of the 1478 patients treated with Calquence monotherapy, the most common (≥ 20%) adverse drugreactions (ADRs) of any grade were infection, diarrhoea, headache, musculoskeletal pain, bruising, cough,arthralgia, fatigue, nausea and rash. The most commonly reported (≥ 5%) Grade ≥ 3 adverse drugreactions were infection, leukopenia, neutropenia, anaemia, second primary malignancy, andthrombocytopenia.

Calquence in combination with obinutuzumab

Of the 223 patients treated with Calquence combination therapy, the most common (≥ 20%) ADRs of anygrade were infection, musculoskeletal pain, diarrhoea, headache, leukopenia, neutropenia, cough, fatigue,arthralgia, nausea, dizziness, and constipation. The most commonly reported (≥ 5%) Grade ≥ 3 adverse drugreactions were leukopenia, neutropenia, infection, thrombocytopenia and anaemia.

Calquence in combination with bendamustine and rituximab

Of the 297 patients treated with Calquence in combination with bendamustine and rituximab, the mostcommon (≥ 20%) ADRs of any grade were neutropenia, nausea, rash, diarrhoea, musculoskeletal pain,headache, fatigue, vomiting, constipation, anaemia and thrombocytopenia. The most commonly reported(≥ 5%) Grade ≥ 3 adverse drug reactions were neutropenia, rash, thrombocytopenia, anaemia, pneumonia,second primary malignancies, hypertension and second primary malignancies excluding non-melanomaskin.

The following adverse drug reactions (ADRs) have been identified in clinical studies with patientsreceiving Calquence as treatment for haematological malignancies. The median duration of Calquencemonotherapy treatment across the pooled dataset was 38.2 months. The median duration of Calquencetreatment in patients treated with Calquence in combination with bendamustine and rituximab was28.6 months.

Adverse drug reactions are listed according to system organ class (SOC) in MedDRA. Within each systemorgan class, the adverse drug reactions are sorted by frequency, with the most frequent reactions first. Inaddition, the corresponding frequency category for each ADR 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). Within each frequency grouping,adverse reactions are presented in order of decreasing seriousness.

Table 4. Adverse drug reactions* of patients with haematological malignancies treated withacalabrutinib monotherapy (N=1478)

All Grades

Grade ≥ 3*

MedDRA SOC MedDRA Term (%) (%)

Upper respiratory tract infection Very common (25.8) 1.2

Pneumonia Very common (15.8) 8.7

Sinusitis Very common (11.4) 0.4

Urinary tract infection Common (9.9) 1.8

Infections and

Bronchitis Common (9.7) 0.6infestations

Herpes viral infections† Common (9.1) 0.9

Nasopharyngitis Common (8.3) 0

Aspergillus infections† Uncommon (0.7) 0.6

Hepatitis B reactivation Uncommon (0.4) 0.3

Neoplasms benign, Second Primary Malignancy (SPM)† Very common (17.6) 6.7malignant and Non-melanoma skin malignancy† Common (9.9) 1.4unspecified SPM excluding non-melanoma skin† Common (9.7) 5.5

Neutropenia† Very common (19.4) 17.5

Blood and Anaemia† Very common (17.1) 9.5lymphatic systemdisorders Thrombocytopenia† Very common (11.5) 6.2

Lymphocytosis Uncommon (0.5) 0.3

Metabolism and

Tumour Lysis Syndrome Uncommon (0.5) 0.4nutrition disorders

Nervous system Headache Very common (36.5) 1.2disorders Dizziness Very common (13.9) 0.1

Cardiac disorders Atrial fibrillation/Flutter† Common (7.4) 2.3

Bruising† Very common (30.9) 0

Contusion Very common (20.7) 0

Petechiae Common (8.9) 0

Ecchymoses Common (5.7) 0

Vascular disorders Haemorrhage/haematoma† Very common (16.3) 3.2

Gastrointestinal haemorrhage Uncommon (0.9) 0.7

Intracranial haemorrhage U ncommon (0.1) 0.1

Hypertension† Very common (11.9) 4.9

Epistaxis Common (8.0) 0.3

All Grades

Grade ≥ 3*

MedDRA SOC MedDRA Term (%) (%)

Diarrhoea Very common (36.7) 2.6

Nausea Very common (21.8) 0.8

Gastrointestinal

Constipation Very common (15.2) 0.1disorders

Abdominal pain† Very common (14.5) 1.2

Vomiting Very common (14.0) 0.7

Skin andsubcutaneous Rash† Very common (20.3) 0.9tissue disorders

Musculoskeletal Musculoskeletal Pain† Very common (31.9) 1.8and connectivetissue disorders Arthralgia Very common (24.0) 0.9

General disorders Fatigue Very common (23.6) 2.0and administrationsite conditions Asthenia Common (7.0) 0.9

Haemoglobin decreased± Very common (47.4) 10.8

Investigations§

Absolute neutrophil count decreased± Very common (43.9) 24.0(Findings based ontest results)

Platelets decreased± Very common (36.9) 9.5

*Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.†Includes multiple ADR term.±Represents the incidence of laboratory findings, not of reported adverse events.§Presented as CTCAE grade values.

Table 5. Adverse drug reactions* of patients with haematological malignancies treated withacalabrutinib combination therapy (N=520)

Calquence + Obinutuzumab Calquence + BR

N=223 N=297

Grade ≥ Grade ≥

MedDRA SOC and MedDRA All Grades All Grades3* 3*

Term (%) (%)(%) (%)

Upper respiratory tract infection Very common (31.4) 1.8 Very common (18.2) 0.3

Sinusitis Very common (15.2) 0.4 Common (6.4) 0

Nasopharyngitis Very common (13.5) 0.4 Common (5.4) 0

Urinary tract infection Very common (13) 0.9 Very common (11.1) 1.7

Calquence + Obinutuzumab Calquence + BR

N=223 N=297

Grade ≥ Grade ≥

MedDRA SOC and MedDRA All Grades All Grades3* 3*

Term (%) (%)(%) (%)

Pneumonia Very common (10.8) 5.4 Very common (16.2) 8.8

Bronchitis Common (9.9) 0 Common (6.4) 0.3

Herpes viral infections† Common (6.7) 1.3 Very common (12.8) 1.0

Progressive multifocal

Uncommon (0.4) 0.4 Not known 0leukoencephalopathy

Hepatitis B reactivation Uncommon (0.9) 0.1 Common (1.3) 0.3

Aspergillus infections† Not known 0 Uncommon (0.3) 0.3

Neoplasms benign, malignant and unspecified

Second primary

Very common (13) 4.0 Very common (17.8) 7.4malignancy†(SPM)

Non-melanoma skin† Common (7.6) 0.4 Very common (11.1) 2.0malignancy

SPM excluding non-melanoma† Common (6.3) 3.6 Common (9.8) 5.4skin

Neutropenia† Very common (31.8) 30 Very common (54.9) 50.2

Thrombocytopenia† Very common (13.9) 9 Very common (22.9) 9.8

Anaemia† Very common (11.7) 5.8 Very common (24.2) 9.4

Lymphocytosis Uncommon (0.4) 0.4 Uncommon (0.7) 0

Tumour lysis syndrome Common (1.8) 1.3 Common (1.3) 1.3

Headache Very common (43) 0.9 Very common (30.3) 1.3

Dizziness Very common (23.8) 0 Very common (14.5) 0.7

Atrial fibrillation/flutter† Common (3.1) 0.9 Common (6.7) 4.0

Calquence + Obinutuzumab Calquence + BR

N=223 N=297

Grade ≥ Grade ≥

MedDRA SOC and MedDRA All Grades All Grades3* 3*

Term (%) (%)(%) (%)

Bruising† Very common (38.6) 0 Very common (14.1) 0.3

Contusion Very common (27.4) 0 Very common (11.1) 0

Petechiae Very common (11.2) 0 Common (2.0) 0

Ecchymoses Common (3.1) 0 Common (3.0) 0.3

Haemorrhage/haematoma† Very common (17.5) 1.3 Very common (15.5) 1.0

Gastrointestinal haemorrhage Common (3.6) 0.9 Uncommon (0.3) 0

Intracranial haemorrhage Uncommon (0.9) 0 Not known 0

Hypertension† Very common (13.5) 3.6 Very common (12.5) 5.7

Epistaxis Common (8.5) 0 Common (2.7) 0

Pneumonitis± - - Common (2.4) 0.3

Diarrhoea Very common (43.9) 4.5 Very common (37.4) 3.0

Nausea Very common (26.9) 0 Very common (42.8) 1.3

Constipation Very common (20.2) 0 Very common (24.6) 1.0

Vomiting Very common (19.3) 0.9 Very common (25.6) 0.7

Abdominal pain† Very common (14.8) 1.3 Very common (12.1) 2.0

Rash† Very common (30.9) 1.8 Very common (39.1) 9.8

Musculoskeletal pain† Very common (44.8) 2.2 Very common (34.3) 3.7

Arthralgia Very common (26.9) 1.3 Very common (17.5) 0.7

Fatigue Very common (30.5) 1.8 Very common (29.3) 2.7

Asthenia Common (7.6) 0.4 Very common (10.4) 1.0

Investigations¶

Absolute neutrophil count

Very common (57.4) 35 Very common (76.8) 56.6decreased§

Calquence + Obinutuzumab Calquence + BR

N=223 N=297

Grade ≥ Grade ≥

MedDRA SOC and MedDRA All Grades All Grades3* 3*

Term (%) (%)(%) (%)

Platelets decreased§ Very common (46.2) 10.8 Very common (69.4) 17.8

Haemoglobin decreased§ Very common (43.9) 9 Very common (79.5) 10.8

Alanine aminotransferase‡ - - Common (9.1) 4.4increased

Aspartate aminotransferase‡ - - Common (8.1) 3.0increased

*Per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.†Includes multiple ADR term.±One event with fatal outcome was reported.§Represents the incidence of laboratory findings, not of reported adverse events.¶Presented as CTCAE grade values.‡Adverse reaction only for the Calquence + BR arm in the ECHO study.

Discontinuation and dose reduction due to adverse reactions

Of the 1478 patients treated with Calquence monotherapy, discontinuation due to adverse reactions werereported in 14.6% of the patients. These main adverse reactions included pneumonia, thrombocytopeniaand diarrhoea. Dose reductions due to adverse reactions were reported in 5.9% of patients. These mainadverse reactions included hepatitis B reactivation, sepsis, and diarrhoea.

Of the 223 patients treated with Calquence in combination with obinutuzumab, discontinuation due toadverse reactions were reported in 10.8% of the patients. These main adverse reactions includedpneumonia, thrombocytopenia and diarrhoea. Dose reductions due to adverse reactions were reported in6.7% of patients. These main adverse reactions included neutropenia, diarrhoea and vomiting.

Of the 297 patients treated with Calquence in combination with bendamustine and rituximab,discontinuation due to adverse reactions were reported in 42.8% of the patients. These main adversereactions included COVID-19, COVID-19 pneumonia, neutropenia and pneumonia. Dose reductions dueto adverse reactions were reported in 10.1% of patients. These main adverse reactions includedneutropenia and nausea.

Of the 1478 patients in clinical studies of Calquence monotherapy, 42% were greater than 65 years andless than 75 years of age and 20.6% were 75 years of age or older. No clinically relevant differences insafety or efficacy were observed between patients ≥ 65 years and younger.

Of the 223 patients in clinical studies of Calquence in combination of obinutuzumab therapy, 47% weregreater than 65 years and less than 75 years of age and 26% were 75 years of age or older. No clinicallyrelevant differences in safety or efficacy were observed between patients ≥ 65 years and younger.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

There is no specific treatment for acalabrutinib overdose and symptoms of overdose have not beenestablished. In the event of an overdose, patients must be closely monitored for signs or symptoms ofadverse reactions and appropriate symptomatic treatment instituted.

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

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-cellsurvival 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.

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.

The effect of acalabrutinib on the QTc interval was evaluated in 46 healthy male and female subjects in arandomised, double-blind thorough QT study with placebo and positive controls. At a supratherapeuticdose, 4-times the maximum recommended dose, Calquence did not prolong the QT/QTc interval to anyclinically relevant extent (e.g., not greater than or equal to 10 ms) (see sections 4.4, pct. 4.8 and 5.3).

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 plusobinutuzumab, Calquence monotherapy, or obinutuzumab plus chlorambucil. Patients 65 years of age orolder, 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 dailystarting on Cycle 1 Day 1 until disease progression or unacceptable toxicity. Obinutuzumab wasadministered starting on Cycle 2 Day 1 for a maximum of 6 treatment cycles. Obinutuzumab1,000 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 progressionor unacceptable toxicity.

* Obinutuzumab plus chlorambucil (GClb): Obinutuzumab and chlorambucil were administered for amaximum 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 performancestatus (0 or 1 versus 2) and geographic region (North America and Western Europe versus Other). Afterconfirmed disease progression, 45 patients randomised on the GClb arm crossed over to Calquencemonotherapy. Table 6 summarises the baseline demographics and disease characteristics of the studypopulation.

Table 6. Baseline patient characteristics in (ELEVATE-TN) patients with previously untreated CLL

Characteristic Calquence plus Calquence Obinutuzumabobinutuzumab monotherapy plus

N=179 N=179 chlorambucil

N=177

Age, years; median (range) 70 (41-88) 70 (44-87) 71 (46-91)

Male; % 62 62 59.9

Caucasian; % 91.6 95 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 911q 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 asassessed 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 a90% 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 Table7.

Table 7. Efficacy results per IRC Assessments in (ELEVATE-TN) patients with CLL

Calquence plus Calquence Obinutuzumabobinutuzumab monotherapy plus

N=179 N=179 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, % 92.7 (87.4, 95.8) 87.3 (80.9, 91.7) 46.7 (38.5, 54.6)(95% CI)

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 (%) 168 (93.9) 153 (85.5) 139 (78.5)(95% CI) (89.3, 96.5) (79.6, 89.9) (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 0nPR, 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=completeresponse 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 highrisk 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 chlorambucilwas 0.08 [95% CI (0.04, 0.15)] and 0.13 [95% CI (0.08, 0.21)], respectively.

Table 8. Subgroup analysis of PFS (Study ELEVATE-TN)

Calquence monotherapy Calquence+G

N Hazard 95% CI N Hazard 95% CI

Ratio Ratio

All 179 0.20 (0.13, 0.30) 179 0.10 (0.06,subjects 0.17)

Calquence monotherapy Calquence+G

N Hazard 95% CI N Hazard 95% CI

Ratio Ratio

Del 17P

Yes 19 0.20 (0.06, 0.64) 21 0.13 (0.04,

No 160 0.20 (0.12, 0.31) 158 0.09 0.46)(0.05,0.17)

TP53mutation

Yes 19 0.15 (0.05, 0.46) 21 0.04 (0.01,

No 160 0.20 (0.12, 0.32) 158 0.11 0.22)(0.06,0.20)

Del 17Por/and

TP53mutation

Yes 23 0.23 (0.09, 0.61) 25 0.10 (0.03,

No 156 0.19 (0.11, 0.31) 154 0.10 0.34)(0.05,0.18)

IGHVmutation

Mutated 58 0.69 (0.31, 1.56) 74 0.15 (0.04,

Unmutated 119 0.11 (0.07, 0.19) 103 0.08 0.52)(0.04,0.16)

Del 11q

Yes 31 0.07 (0.02, 0.22) 31 0.09 (0.03,

No 148 0.26 (0.16, 0.41) 148 0.10 0.26)(0.05,0.20)

Complex

Karyotype

Yes 31 0.10 (0.03, 0.33) 29 0.09 (0.03,

No 117 0.27 (0.16, 0.46) 126 0.11 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 thetime of most recent data cut off, a total of 72 patients (40.7%) originally randomised to the GClb armcrossed over to Calquence monotherapy. The median overall survival had not been reached in any armwith a total of 76 deaths: 18 (10.1%) in the Calquence+G arm, 30 (16.8%) in the Calquence monotherapyarm, and 28 (15.8%) in the GClb arm.

Table 9. Efficacy Results per INV assessment in (ELEVATE-TN) Patients with CLL

Calquence plus Calquence Obinutuzumab plusobinutuzumab monotherapy Chlorambucil

N=179 N=179 N=177

Progression-freesurvival

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), NR NR (66.5, NR) 27.8 (22.6, 33.2)months*

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% 0.55 (0.30, 0.99) 0.98 (0.58, 1.64) -

CI) †

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 deletionstatus (yes vs no).

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

Population)

Calquence+G

Calquence

GClb

Time from randomisation (months)

Month 0 3 6 9 12 15 18 2 1 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 70

Calquence 179 167 163 158 156 155 153 150 149 146 142 141 137 135 133 130 129 124 120 93 63 39 22 6 1

Calquence+G 179 175 170 168 164 163 160 157 156 156 153 152 151 146 144 141 140 138 133 99 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 20 13 8 7 2 0

Progression free survival (%)

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 therapynot including BCL-2 inhibitors or B-cell receptor inhibitors. Patients received Calquence monotherapy orinvestigator’s choice of either idelalisib plus rituximab or bendamustine plus rituximab. The study allowedpatients to receive antithrombotic agents. Patients who required anticoagulation with warfarin orequivalent 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:

o Idelalisib 150 mg twice daily in combination with rituximab 375 mg/m2 IV on Day 1 of the firstcycle, followed by 500 mg/m2 IV every 2 weeks for 4 doses, then every 4 weeks for 3 doses fora total of 8 infusionso 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 performancestatus (0 or 1 versus 2) and number of prior therapies (1 to 3 versus ≥ 4). After confirmed diseaseprogression, 35 patients randomised on investigator’s choice of either idelalisib plus rituximab orbendamustine plus rituximab crossed over to Calquence. Table 10 summarizes the baseline demographicsand disease characteristics of the study population.

Table 10. Baseline patient characteristics in (ASCEND) patients with CLL

Characteristic Calquence Investigator’s choice ofmonotherapy idelalisib + rituximab or

N=155 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 35.51 50.3 51.02 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 43.22 25.8 29.73 11.0 15.5≥ 4 10.3 11.6

Cytogenetics/FISH Category; %17p deletion 18.1 13.511q deletion 25.2 28.4

Characteristic Calquence Investigator’s choice ofmonotherapy idelalisib + rituximab or

N=155 bendamustine +rituximab

N=155

TP53 mutation 25.2 21.9

Unmutated IGHV 76.1 80.6

Complex karyotype (≥3 abnormalities) 32.3 29.7

Rai Stage; %0 1.3 2.6

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 theclarification 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 11. The Kaplan-Meier curve for PFS is shown in

Figure 2.

Table 11. Efficacy results per IRC Assessments in (ASCEND) patients with CLL

Calquence monotherapy Investigator’s choice of

N=155 idelalisib + rituximab orbendamustine + 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 < 0.000115 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 (%) 126 (81.3) 117 (75.5)(95% CI) (74.4, 86.6) (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 withincomplete blood count recovery; nPR=nodular partial response; PR=partial response; PD=progressive disease

*Per IRC assessmenta 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)

Calquence

Investigator’s Choice

Time from randomisation (months)

Number of patients at risk

Month 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Calquence 155 153 153 149 147 146 145 143 143 139 139 137 118 116 73 61 60 25 21 21 1 1 1 0

Investigator’s 155 150 150 146 144 142 136 130 129 112 105 101 82 77 56 44 39 18 10 8 0

Choice

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 12. Subgroup analysis of IRC-assessed PFS (Study ASCEND)

Calquence monotherapy

N Hazard Ratio 95% CI

All subjects 155 0.30 (0.19, 0.48)

Del 17P

Yes 28 0.21 (0.07, 0.68)(0.21, 0.54)

No 127 0.33

TP53 mutation

Yes 39 0.24 (0.11, 0.56) (0.20, 0.57)

No 113 0.33

Del 17P or TP53 mutation

Yes 45 0.21 (0.09, 0.48) (0.21, 0.61)

No 108 0.36

Progression free survival (%)

Calquence monotherapy

N Hazard Ratio 95% CI

IGHV mutation

Mutated 33 0.32 (0.11, 0.94) (0.19, 0.52)

Unmutated 118 0.32

Del 11q

Yes 39 0.28 (0.11, 0.70) (0.19, 0.53)

No 116 0.31

Complex Karyotype

Yes 50 0.32 (0.16, 0.63) (0.12, 0.44)

No 97 0.23

At final analysis, with a median follow-up of 46.5 months for Calquence and 45.3 months for the IR/BR, a72% reduction in risk of investigator-assessed disease progression or death was observed for patients inthe Calquence arm. The median investigator assessed PFS was not reached in Calquence and was 16.8months in IR/BR. Efficacy results per Investigator Assessments (INV) are presented in Table 13. The

Kaplan-Meier curve for INV assessed PFS is shown in Figure 3.

Table 13. Efficacy results at final analysis per INV assessments in (ASCEND) patients with CLL

Calquence monotherapy Investigator’s choice of idelalisib +

N=155 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

Calquence

Investigator’s Choice

Time from randomization (months)

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 32 28 26 23 12 5 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.

Patients with previously untreated MCL

The safety and efficacy of Calquence in patients with previously untreated MCL was evaluated in ECHO,a randomised, double-blind, placebo-controlled, multi-centre, phase 3 study. ECHO included 598 patients65 years of age and older with confirmed MCL that was previously untreated.

Patients were randomised in 1:1 ratio in 2 arms to receive:

* Calquence plus bendamustine and rituximab (Calquence + BR) arm - Calquence 100 mg wasadministered twice daily from Day 1 of Cycle 1, continuously. Bendamustine, 90 mg/m2, wasintravenously administered over 30 minutes on Days 1 and 2 of each of six 28-day cycles; andrituximab, 375 mg/m2, was intravenously administered on Day 1 of each cycle of six 28-daycycles. Calquence + BR was administered for a maximum of 6 treatment cycles (inductiontreatment).

* Placebo plus bendamustine and rituximab (Placebo + BR) arm - Placebo was administered twicedaily from Day 1 of Cycle 1, continuously. Bendamustine, 90 mg/m2, was intravenouslyadministered 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.

Placebo + BR was administered for a maximum of 6 treatment cycles (induction treatment).

Progression-Free survival (%)

Calquence or placebo was administered continuously until disease progression or unacceptable toxicity.

After the induction treatment, patients who were achieving a response (PR or CR) received rituximabmaintenance at 375 mg/m2 on Day 1 of every other cycle for maximum of 12 additional doses up to Cycle30. 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 unacceptabletoxicity.

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 4-5versus 6-11).

The median age was 71 years (65-86), 70.7% were males, 78.3% were Caucasians, 93.1% had an ECOGperformance 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 wereseen in 7.7% and 5.5% of patients respectively. A total of 47.8% patients had Ki-67 score of ≥ 30%. Thebaseline characteristics were similar for both arms.

The primary endpoint was progression-free survival (PFS) as assessed by an Independent Review

Committee (IRC) per 2014 Lugano Classification for non-Hodgkin’s lymphoma (NHL) in subjects withpreviously untreated MCL. Additionally, overall response rate (ORR) was also assessed by an IRC.

IRC-assessed PFS was assessed at a median follow-up of 49.8 months.

With an additional 6 months of follow-up from the primary PFS analysis, and a median follow-up of63.0 months, the median overall survival had not been reached in either arm. There were a total of 218deaths: 105 (35.1%) in the Calquence + BR arm and 113 (37.8%) in the placebo + BR arm. Efficacyresults are presented in Table 14. The Kaplan-Meier curves for PFS are shown in Figure 4.

Table 14. Efficacy Results in Patients with previously untreated MCL in ECHO

Calquence + BR Placebo + BR

N=299 N=299

IRC-assessed PFS

Median (95% CI) 66.4 (55.1, NE) 49.6 (36.0, 64.1)

HR (95% CI) (stratified)* 0.73 (0.57, 0.94)p-value‡ 0.0160

IRC-assessed ORR

CR + PR n (%) 272 (91.0) 263 (88.0)95% CI 87.3,93.8 83.9, 91.3

CR n (%) 199 (66.6) 160 (53.5)

PR n (%) 73 (24.4) 103 (34.4)p-value 0.2196 -

HR = hazard ratio, CR = complete response, PR = partial response, NE = not evaluable

*Stratified by randomisation stratification factors: Geographic Regions (North American, Western Europe, Other)and simplified MIPI Score (Low risk [0 to 3], Intermediate risk [4 to 5], High Risk [6 to 11]) as collected via IXRS.

Estimated based on stratified Cox Proportional Hazards model for hazard ratio (95% CI).‡ Estimated based on stratified log-rank test for p-value.

Figure 4. Kaplan-Meier Curve of IRC-Assessed PFS in patients with previously untreated MCL(ECHO)

Calquence + BR

Placebo + BR

Months

Number at risk

Calquence + BR

Placebo + BR

Patients with MCL who received at least one prior therapy

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 didnot include patients who received prior treatment with either BTK or BCL-2 inhibitors. The primaryendpoint 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. Efficacyresults at final (54 months) analysis are presented in Table 15.

At final analysis, 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 timesince 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 longestdiameter ≥ 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 andwhite cell count) was intermediate in 43.5% and high in 16.9% of patients.

Progression-Free Survival (%)

Table 15. ORR and DOR in (ACE-LY-004) Patients with MCL at 54 months final analysis

Investigator Assessment at 54 months

N=124n (%) (95% CI*)

Overall Response Rate (ORR)

Overall Response Rate 101 (81.5%) (73.5, 87.9)

Complete Response 59 (47.6%) (38.5, 56.7)

Partial Response 42 (33.9%) (25.6, 42.9)

Non-Evaluable† 3 (2.4%) (0.5, 6.9)

Duration of Response (DoR)

Median (months) 28.6 (17.5, 39.1)

CI=Confidence Interval

*95% exact binomial confidence interval.†Includes subjects without any adequate post-baseline disease assessment.

The European Medicines Agency has waived the obligation to submit the results of studies with

Calquence in all subsets of the paediatric population for the treatment of mature B-cell neoplasms (forinformation on paediatric use, see section 4.2).

The pharmacokinetics (PK) of acalabrutinib and its active metabolite, ACP-5862, were studied in healthysubjects and in patients with B-cell malignancies. Acalabrutinib exhibits dose-proportionality, and bothacalabrutinib and ACP-5862 exhibit almost linear PK across a dose range of 75 to 250 mg. Population PKmodelling suggests that the PK of acalabrutinib and ACP-5862 is similar across patients with different B-cell 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 timecurve (AUC24h) and maximum plasma concentration (Cmax) for acalabrutinib were 1679 ng*h/mL and438 ng/mL, respectively, and for ACP-5862 were 4166 ng*h/mL and 446 ng/mL, respectively.

The time to peak plasma concentrations (Tmax) was 0.5-1.5 hours for acalabrutinib, and 1.0 hour for ACP-5862. The absolute bioavailability of Calquence was 25%.

Effect of food on acalabrutinib

In healthy subjects, administration of a single 75 mg dose of acalabrutinib with a high fat, high caloriemeal (approximately 918 calories, 59 grams carbohydrate, 59 grams fat and 39 grams protein) did notaffect the mean AUC as compared to dosing under fasted conditions. Resulting Cmax decreased by 69%and Tmax was delayed 1-2 hours.

Reversible binding to human plasma protein was 99.4% for acalabrutinib and 98.8% for ACP-5862. Thein vitro mean blood-to-plasma ratio was 0.8 for acalabrutinib and 0.7 for ACP-5862. The mean steadystate 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 byglutathione conjugation and amide hydrolysis. ACP-5862 was identified as the major metabolite inplasma, that was further metabolized primarily by CYP3A-mediated oxidation, with a geometric meanexposure (AUC) that was approximately 2- to 3-fold higher than the exposure of acalabrutinib. ACP-5862is 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 affectclearance 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 isunlikely 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. Co-administration 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 increasein acalabrutinib Cmax and AUC by 1.2-fold and 1.4-fold (N=24, healthy subjects), respectively, which isnot 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 ACP-5862 may inhibit MATE1 at clinically relevant concentrations (see section 4.5). Acalabrutinib does notinhibit MATE1, while ACP-5862 does not inhibit BCRP at clinically relevant concentrations.

Following a single oral dose of 100 mg acalabrutinib, the terminal elimination half-life (t1/2) ofacalabrutinib was 1 to 2 hours. The t1/2 of the active metabolite, ACP-5862, was approximately 7 hours.

The mean apparent oral clearance (CL/F) was 134 L/hr for acalabrutinib and 22 L/hr for ACP-5862 inpatients 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 lessthan 2% of the dose excreted as unchanged acalabrutinib.

Based on population PK analysis, age (>18 years of age), sex, race (Caucasian, African American) andbody weight did not have clinically meaningful effects on the PK of acalabrutinib and its activemetabolite, ACP-5862.

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 renalimpairment has not been conducted.

Based on population PK analysis, no clinically relevant PK difference was observed in 408 subjects withmild renal impairment (eGFR between 60 and 89 mL/min/1.73m2 as estimated by MDRD), 109 subjectswith moderate renal impairment (eGFR between 30 and 59 mL/min/1.73m2) relative to 192 subjects withnormal renal function (eGFR greater than or equal to 90 mL/min/1.73m2). The pharmacokinetics ofacalabrutinib has not been characterised in patients with severe renal impairment (eGFR less than29 mL/min/1.73m2) or renal impairment requiring dialysis. Patients with creatinine levels greater than 2.5times the institutional ULN were not included in the clinical studies (see section 4.2).

Acalabrutinib is metabolised in the liver. In dedicated hepatic impairment (HI) studies, compared tosubjects 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 howevernot significantly affected in markers relevant for the elimination capacity of drugs, so the effect ofmoderate 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 withnormal (n=613) hepatic function (total bilirubin and AST within ULN) (see section 4.2).

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 chromosomeaberration 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 riskfor phototoxicity in humans.

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 minimalto mild severity in the kidneys (tubular basophilia, tubular regeneration, and inflammation) were observedin studies of up to 6-month duration with a No Observed Adverse Effect level (NOAEL) of 30 mg/kg/dayin 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 tubulardegeneration) and liver (individual hepatocyte necrosis) findings were observed in the chronic rat studywas 100 mg/kg/day and provided an exposure margin 4.2-times greater than the clinical exposure at therecommended dose of 100 mg twice daily. In studies of 9 months duration in dogs, the NOAEL was10 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 milddecreases in red cell mass and increases in ALT and ALP were observed at 30 mg/kg/day (9-times theclinical AUC) in dogs. Cardiac toxicities in rats (myocardial haemorrhage, inflammation, necrosis) anddogs (perivascular/vascular inflammation) were observed only in animals that died during studies at dosesabove the maximum tolerated dose (MTD). The exposures in rats and dogs with cardiac findings was atleast 6.8-times and 25-times the clinical AUC, respectively. Reversibility for the heart findings could notbe assessed as these findings were only observed at doses above the MTD.

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

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

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

AUC at the recommended dose.

Microcrystalline cellulose

Colloidal anhydrous silica

Partially pregelatinised maize starch

Magnesium stearate (E470b)

Sodium starch glycollate

Gelatine

Titanium dioxide (E171)

Yellow iron oxide (E172)

Indigo carmine (E132)

Shellac

Black iron oxide (E172)

Propylene glycol (E1520)

Ammonium hydroxide

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Aluminium/Aluminium blisters with sun/moon symbols containing 6 or 8 hard capsules. Cartons of 56 or60 capsules.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

AstraZeneca AB

SE-151 85 Södertälje

Sweden

EU/1/20/1479/001

EU/1/20/1479/002

Date of first authorisation: 05 November 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.