Acalabrutinib

Acalabrutinib is a selective inhibitor of Bruton tyrosine kinase (BTK) that works by covalent binding. BTK is a signalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways; its signals promote the survival, proliferation, adhesion and trafficking of B-cells, including the malignant B-cells of chronic lymphocytic leukaemia and mantle cell lymphoma.

Mechanism of Action

• Covalent, irreversible inhibition: acalabrutinib and its active metabolite ACP-5862 bind covalently to a cysteine residue (Cys481) in the BTK active site, inactivating the enzyme irreversibly with minimal off-target interactions. This blocks activation of downstream proteins such as CD86 and CD69 and inhibits the proliferation and survival of malignant B-cells.
• Active metabolite: ACP-5862, the main metabolite in plasma, is about 50% less potent than acalabrutinib against BTK, but its exposure is 2 to 3 times higher.
• Cardiac electrophysiology: in a thorough QT study in 46 healthy volunteers, a dose 4 times the maximum recommended dose did not prolong the QT/QTc interval to a clinically relevant extent.

Pharmacokinetics

• Absorption: absolute bioavailability is 25%, with peak plasma levels after 0.5 to 1.5 hours. Exposure is close to dose-proportional between 75 and 250 mg. A high-fat meal left the area under the concentration–time curve (AUC) unchanged but lowered the peak concentration by 69% and delayed it by 1 to 2 hours, so the capsules can be taken with or without food.
• Distribution: reversible plasma protein binding is 99.4% for acalabrutinib and 98.8% for ACP-5862. The steady-state volume of distribution is about 34 L.
• Metabolism: mainly by CYP3A enzymes, with minor glutathione conjugation and amide hydrolysis. ACP-5862 is further metabolised mainly by CYP3A-mediated oxidation. Both are substrates of P-gp and BCRP.
• Elimination: after a single radiolabelled 100 mg dose, 84% of the radioactivity was recovered in faeces and 12% in urine. The median terminal half-life is about 0.9 hours for acalabrutinib and about 6.9 hours for ACP-5862.
• Special populations: pharmacokinetics are similar across patients with different B-cell malignancies.

Acalabrutinib is indicated in adults:

• Chronic lymphocytic leukaemia (CLL), previously untreated: as monotherapy or in combination with obinutuzumab; or in combination with venetoclax, with or without obinutuzumab.
• CLL, previously treated: as monotherapy in patients who have received at least one prior therapy.
• Mantle cell lymphoma (MCL), previously untreated: in combination with bendamustine and rituximab in patients who are not eligible for autologous stem cell transplant (ASCT).
• MCL, relapsed or refractory: as monotherapy in patients not previously treated with a BTK inhibitor.

• Hypersensitivity to acalabrutinib or to any of the excipients.

The data come from clinical studies in haematological malignancies, including 1,478 patients treated with acalabrutinib alone. With monotherapy, each of the following affected at least 20% of patients: infections, diarrhoea, headache, musculoskeletal pain, bruising, cough, arthralgia, fatigue, nausea and rash. The most common reactions of grade 3 or higher (at least 5%) were infection, leukopenia, neutropenia, anaemia, second primary malignancy and thrombocytopenia.

Very common (≥1/10): infections (including upper respiratory tract infection, pneumonia and sinusitis), second primary malignancy (including non-melanoma skin cancer), neutropenia, anaemia, thrombocytopenia, headache, dizziness, bruising (including contusion), haemorrhage or haematoma, hypertension, cough, diarrhoea, nausea, constipation, abdominal pain, vomiting, rash, musculoskeletal pain, arthralgia, fatigue, peripheral oedema and, in blood tests, decreased haemoglobin, decreased neutrophil count and decreased platelet count. With combination regimens, the following affected at least 20% of patients: leukopenia, neutropenia, dizziness and constipation (with obinutuzumab); neutropenia (with venetoclax, with or without obinutuzumab); and neutropenia, anaemia, thrombocytopenia, vomiting and constipation (with bendamustine and rituximab).

Common (≥1/100 to <1/10): urinary tract infection, bronchitis, herpes viral infections, nasopharyngitis, non-melanoma skin cancer, second primary malignancy other than non-melanoma skin cancer, atrial fibrillation or flutter, petechiae, ecchymosis, epistaxis, asthenia.

Uncommon (≥1/1,000 to <1/100): Aspergillus infections, hepatitis B reactivation, lymphocytosis, tumour lysis syndrome, gastrointestinal haemorrhage, intracranial haemorrhage.

These lists follow the monotherapy table; the SmPC gives separate tables for the combination regimens.

Important serious reactions are major haemorrhage (some fatal), serious infections (including hepatitis B and herpes zoster reactivation, aspergillosis and progressive multifocal leukoencephalopathy, some fatal), grade 3 or 4 cytopenias, second primary malignancies (including non-melanoma skin cancers) and atrial fibrillation or flutter.

Acalabrutinib and its active metabolite are metabolised mainly by CYP3A4 and are substrates of P-gp and BCRP, so strong inhibitors and inducers of CYP3A change exposure substantially.

• Strong CYP3A/P-gp inhibitors (ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole, ritonavir, telaprevir, posaconazole, voriconazole): itraconazole raised the peak concentration 3.9-fold and the AUC 5.0-fold. Avoid; if a strong inhibitor is needed for a short time, interrupt acalabrutinib.
• Moderate CYP3A inhibitors (for example fluconazole, isavuconazole): acalabrutinib exposure rose 1.4- to 2-fold. No dose adjustment, but monitor closely for adverse reactions.
• Strong CYP3A inducers (phenytoin, rifampicin, carbamazepine): rifampicin lowered the peak concentration by 68% and the AUC by 77%. Avoid these, and also St John’s wort, which may lower levels unpredictably.
• Gastric acid-reducing medicines: acalabrutinib dissolves less well as pH rises, so medicines that raise stomach pH may reduce absorption. Take antacids at least 2 hours before or after acalabrutinib; see the SmPC for other acid-reducing medicines. This advice comes from the capsule SmPC; the tablets contain acalabrutinib as the maleate, and the tablet SmPC (section 4.5) applies to them.
• Antithrombotic agents: they may add to the risk of bleeding, so use with caution and consider extra monitoring. Warfarin and other vitamin K antagonists should not be given with acalabrutinib.
• Food: grapefruit and grapefruit products inhibit CYP3A and should be avoided.

Treatment should be started and supervised by a physician experienced in the use of anticancer medicines. The capsules or tablets are swallowed whole with water at about the same time each day, with or without food. Capsules must not be chewed, dissolved or opened, as this may affect absorption; tablets must not be chewed, crushed, dissolved or divided.

Recommended Dose

• 100 mg twice daily (200 mg per day), about 12 hours apart, alone or in combination, taken as one 100 mg capsule or one 100 mg film-coated tablet each time. Partner medicines are dosed according to their own SmPCs.
• Monotherapy, or with obinutuzumab (CLL): until disease progression or unacceptable toxicity.
• With venetoclax, with or without obinutuzumab (untreated CLL): until progression, unacceptable toxicity or completion of 14 cycles of 28 days. Acalabrutinib starts on day 1 of cycle 1. Venetoclax starts on day 1 of cycle 3 and is given for 12 cycles, beginning at 20 mg and increasing weekly to 50 mg, 100 mg, 200 mg and finally 400 mg. Obinutuzumab, if added, is given for 6 cycles: 100 mg on day 1 of cycle 2, then 900 mg on day 1 or 2, then 1,000 mg on days 8 and 15 of cycle 2 and on day 1 of cycles 3 to 7.
• With bendamustine and rituximab (untreated MCL): until progression or unacceptable toxicity, in 28-day cycles from cycle 1. Bendamustine 90 mg/m² on days 1 and 2 and rituximab 375 mg/m² on day 1 of each cycle, for 6 cycles. After a partial or complete response, maintenance rituximab 375 mg/m² may follow on day 1 of every other cycle (up to 12 additional doses, cycle 8 to cycle 30).

Dose Adjustments

• Dose modifications for adverse reactions are given in section 4.2 of the SmPC and decided by the treating physician.
• Surgery: consider the benefit and risk of withholding acalabrutinib for at least 3 days before and after surgery.
• Suspected PML: suspend treatment until it is excluded (see Special Instructions).

Special Populations

• Elderly (65 years and older): no dose adjustment.
• Renal impairment: no dose adjustment for mild or moderate impairment (creatinine clearance above 30 mL/min); maintain hydration and monitor serum creatinine periodically. In severe impairment use only if the benefit outweighs the risk, with close monitoring; there are no data in severe impairment or on dialysis.
• Hepatic impairment: no dose adjustment for mild or moderate impairment (Child-Pugh A or B), but monitor patients with moderate impairment closely for toxicity. Not recommended in severe impairment (Child-Pugh C).
• Severe cardiac disease: patients with severe cardiovascular disease were excluded from the clinical studies.
• Children and adolescents (0 to 18 years): safety and efficacy have not been established.

Haemorrhage

Major haemorrhagic events, including central nervous system and gastrointestinal bleeding, some fatal, have occurred with or without thrombocytopenia; most bleeding events were less severe, such as bruising and petechiae. Antithrombotic agents may increase the risk: use them with caution and consider extra monitoring. Warfarin and other vitamin K antagonists should not be given with acalabrutinib.

Infections and Viral Reactivation

Serious bacterial, viral and fungal infections, some fatal, have occurred, mostly in patients without neutropenia; neutropenic infection was reported in 10.1% of patients on monotherapy and 26.8% on combination therapy. Reactivation of hepatitis B virus (HBV) and herpes zoster virus, aspergillosis and progressive multifocal leukoencephalopathy (PML) have occurred.

• Hepatitis B: establish HBV status before treatment. Patients with positive serology should see a liver disease expert before starting and then be monitored and managed to prevent reactivation.
• PML: fatal cases have been reported after prior or concomitant immunosuppressive therapy. Consider PML in patients with new or worsening neurological, cognitive or behavioural signs or symptoms, and suspend treatment until it is excluded; if in doubt, consider neurologist referral, MRI and cerebrospinal fluid testing for JC virus DNA.
• Prophylaxis: consider prophylaxis according to standard of care in patients at increased risk of opportunistic infections, and monitor for signs of infection.

Cytopenias

Grade 3 or 4 neutropenia, anaemia and thrombocytopenia occurred with acalabrutinib alone or in combination. Complete blood counts should be monitored as medically indicated.

Pregnancy, Breastfeeding and Fertility

• Women of childbearing potential: should be advised to avoid becoming pregnant during treatment.
• Pregnancy: there are no or limited data. Animal studies indicate a possible risk to the foetus (difficult or prolonged labour in rats; reduced foetal growth in rabbits). Do not use during pregnancy unless the woman’s condition requires treatment with acalabrutinib.
• Breastfeeding: a risk to the infant cannot be excluded (the drug and its metabolite were present in rat milk). Mothers should not breastfeed during treatment and for 2 days after the last dose.
• Fertility: there are no human data; no adverse effects on fertility were seen in rats of either sex.

Effect on Driving

Acalabrutinib has no or negligible influence on the ability to drive and use machines. Fatigue and dizziness have been reported; patients who have them should not drive or use machines until the symptoms ease.

Calquence capsules and film-coated tablets do not require any special storage conditions. The capsules are supplied in aluminium/aluminium blisters in cartons of 56 or 60 capsules (not all pack sizes may be marketed). Keep out of the sight and reach of children.

3 years for both the capsules and the tablets. Do not use after the expiry date stated on the pack.

Prescription only (Rx), subject to restricted medical prescription: treatment is started and supervised by a physician experienced in the use of anticancer medicines. Acalabrutinib is taken at home, so it is supplied to the patient or to the treating clinic on prescription.