Inotuzumab Ozogamicin

Inotuzumab ozogamicin is a CD22-directed antibody-drug conjugate (ADC). Leukaemic cells carry lineage-specific antigens, and CD22, found on mature and immature B cells, is one of the most common. The antibody is a recombinant humanised IgG4 kappa antibody made in Chinese hamster ovary cells. It is covalently linked, through an acid-cleavable linker, to N-acetyl-gamma-calicheamicin dimethylhydrazide, a cytotoxic product.

Mechanism of Action

• Binding and internalisation: the antibody part specifically recognises human CD22. After it binds CD22-expressing tumour cells, the ADC–CD22 complex is taken up into the cell.
• Release of the cytotoxin: inside the cell, hydrolytic cleavage of the linker releases N-acetyl-gamma-calicheamicin dimethylhydrazide.
• DNA damage: the released agent binds the minor groove of DNA and induces double-stranded DNA breaks, followed by cell-cycle arrest and apoptotic cell death.
• QT interval: prolongation of the QT interval was seen in clinical studies (see Special Instructions).
• Immunogenicity: 7 of 236 adults (3%) tested positive for anti-drug antibodies, none for neutralising antibodies, with no effect on clearance. None of 51 paediatric patients tested positive.

Pharmacokinetics

• Exposure: at the starting dose of 1.8 mg/m² per cycle, steady-state exposure is reached by Cycle 4. The mean (SD) peak serum concentration was 308 ng/mL (362), and the simulated total AUC per cycle at steady state was 100 mcg·h/mL (SD 32.9). Exposure built up about 5.3-fold between Cycles 1 and 4.
• Distribution: total volume of distribution about 12 L. The released N-acetyl-gamma-calicheamicin dimethylhydrazide is about 97% bound to human plasma proteins in vitro and is a P-glycoprotein substrate.
• Metabolism: in vitro, the calicheamicin derivative is mainly reduced non-enzymatically. In patients its serum levels were typically below the 50 pg/mL limit of quantitation, with sporadic measurable levels of unconjugated calicheamicin up to 276 pg/mL. The antibody part is thought to be degraded to amino acids.
• Elimination: a two-compartment model with linear and time-dependent clearance fits the data. In 234 patients, clearance at steady state was 0.0333 L/h and the terminal half-life at the end of Cycle 4 was about 12.3 days. Body surface area significantly affects disposition, which is why the dose is based on it.
• Special populations: age, race and gender did not significantly affect disposition. No formal pharmacokinetic studies have been done in hepatic impairment.

• Adults: monotherapy for relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukaemia (ALL). Patients with Philadelphia chromosome positive (Ph+) relapsed or refractory B-cell precursor ALL should have failed treatment with at least 1 tyrosine kinase inhibitor (TKI).
• Paediatric patients aged 1 year and older: monotherapy for CD22-positive B-cell precursor ALL in first relapse after allogeneic haematopoietic stem cell transplant (HSCT); after any first relapse in patients with Very High Risk (VHR) disease; after a second or greater relapse; and in refractory disease. Patients with Ph+ disease should have exhausted relevant BCR-ABL targeting treatment options.

• Hypersensitivity to the active substance or to any of the excipients.
• Prior confirmed severe or ongoing veno-occlusive liver disease/sinusoidal obstruction syndrome (VOD/SOS).
• Serious ongoing hepatic disease (for example cirrhosis, nodular regenerative hyperplasia or active hepatitis).

The most common reactions (20% or more) in adults were thrombocytopenia (51%), neutropenia (49%), infection (48%), anaemia (36%), leukopenia (35%), fatigue (35%), haemorrhage (33%), pyrexia (32%), nausea (31%), headache (28%), febrile neutropenia (26%), raised transaminases (26%), abdominal pain (23%), raised gamma-glutamyltransferase (21%) and hyperbilirubinaemia (21%). The most common serious reactions (2% or more) were infection (23%), febrile neutropenia (11%), haemorrhage (5%), abdominal pain (3%), pyrexia (3%), VOD/SOS (2%) and fatigue (2%). The groups below are for adults with relapsed or refractory ALL and count all-cause events.

Very common (≥1/10): infection (including sepsis and bacteraemia, lower and upper respiratory tract, fungal, viral, gastrointestinal, skin and bacterial infections), febrile neutropenia, neutropenia, thrombocytopenia, leukopenia, lymphopenia, anaemia, decreased appetite, headache, haemorrhage (including epistaxis, upper and lower gastrointestinal haemorrhage and central nervous system haemorrhage), abdominal pain, vomiting, diarrhoea, nausea, stomatitis, constipation, hyperbilirubinaemia, raised transaminases, raised gamma-glutamyltransferase, raised alkaline phosphatase, pyrexia, fatigue, chills, infusion-related reaction.

Common (≥1/100 to <1/10): pancytopenia, hypersensitivity, tumour lysis syndrome, hyperuricaemia, ascites, abdominal distension, VOD/SOS (3% before transplant), prolonged QT interval on ECG, raised amylase, raised lipase.

No reactions are listed in the less frequent categories of the adult SmPC table.

Paediatric patients: in 53 patients aged 1 to under 18 years, the most common reactions (over 30%) were thrombocytopenia (51%), pyrexia (49%), anaemia (45%), vomiting (45%), neutropenia (40%), infection (38%), haemorrhage (36%), leukopenia (32%) and nausea (32%). The most common serious reactions (2% or more) were febrile neutropenia (15%), VOD (15%) and infection (13%). In the SmPC’s paediatric table, tumour lysis syndrome (11%) and veno-occlusive disease (15%) are among the very common reactions, while hyperbilirubinaemia, chills, QT prolongation and infusion-related reactions are common.

Important serious reactions:

• VOD/SOS: in the adult pivotal study (164 patients) it occurred in 23 (14%), including 5 (3%) without an intervening transplant. Of 79 patients who went on to HSCT, 18 (23%) developed VOD/SOS, and 5 of these events were fatal. In children it occurred in 8 of 53 (15%), and in 5 of 26 who were transplanted (19%).
• Infections and bleeding: fatal infections occurred in 8 adults (5%); grade 3 or 4 haemorrhagic events occurred in 5% of adults, with one fatal intra-abdominal haemorrhage.
• Infusion-related reactions (10% of adults, all grade 2 or lower) generally occurred in Cycle 1, shortly after the end of the infusion. Tumour lysis syndrome (2%) can be life-threatening or fatal.

No interaction studies have been performed.

• Enzymes and transporters: from in vitro data, inhibitors or inducers of cytochrome P450 (CYP) or UGT enzymes are unlikely to change exposure to N-acetyl-gamma-calicheamicin dimethylhydrazide. Inotuzumab ozogamicin and this cytotoxic part are also unlikely to change exposure to CYP substrates, and the cytotoxic part is unlikely to change exposure to UGT substrates or major drug transporters.
• QT-prolonging medicines: because QT prolongation occurred, combining inotuzumab ozogamicin with medicinal products known to prolong the QT interval or to induce torsades de pointes should be carefully considered, and the QT interval should be monitored when they are combined.
• Live viral vaccines: not recommended from at least 2 weeks before treatment, during treatment, and until B lymphocytes have recovered after the last cycle (see Special Instructions).

Besponsa should be given under the supervision of a physician experienced in cancer therapy and in a setting where full resuscitation facilities are immediately available. Before treatment for relapsed or refractory B-cell ALL, baseline CD22 positivity of more than 0% on a validated and sensitive assay is required.

Before and During the Infusion

• Circulating lymphoblasts: cytoreduction with hydroxycarbamide, steroids and/or vincristine to a peripheral blast count of 10,000/mm³ or less is recommended before the first dose.
• Premedication: a corticosteroid, an antipyretic and an antihistamine before dosing. For a high tumour burden, premedication to reduce uric acid levels and hydration are recommended.
• Observation: patients are observed during the infusion and for at least 1 hour afterwards for infusion-related reactions.
• Infusion: intravenous, over 1 hour; the infusion time is increased to 1.5 hours in paediatric patients weighing less than 35 kg to mitigate QT prolongation. It must not be given as an intravenous push or bolus. It is reconstituted and diluted before use (see section 6.6 of the SmPC).

Recommended Dose

Treatment is given in 3- to 4-week cycles with doses on Days 1, 8 and 15 (Days 8 and 15 may vary by 2 days, keeping at least 6 days between doses). The same regimen applies to adults and paediatric patients.

• Cycle 1 (all patients): total dose 1.8 mg/m² per cycle, as 0.8 mg/m² on Day 1, 0.5 mg/m² on Day 8 and 0.5 mg/m² on Day 15. The cycle lasts 21 days and may be extended to 28 days if the patient achieves a complete remission (CR) or complete remission with incomplete haematological recovery (CRi), and/or to allow recovery from toxicity.
• Later cycles (28 days): patients who have achieved CR or CRi receive 1.5 mg/m² per cycle, as 0.5 mg/m² on each of Days 1, 8 and 15. Patients who have not achieved CR or CRi receive 1.8 mg/m² per cycle (0.8, 0.5 and 0.5 mg/m²).
• Number of cycles: for patients proceeding to HSCT, 2 cycles are recommended, and a third may be considered if they do not reach CR or CRi with minimal residual disease (MRD) negativity after 2 cycles. For patients not proceeding to HSCT, up to 6 cycles may be given. Treatment is discontinued if CR or CRi is not reached within 3 cycles.
• CR means fewer than 5% blasts in the bone marrow, no leukaemic blasts in the blood, full recovery of blood counts (platelets at least 100 × 10⁹/L and neutrophils at least 1 × 10⁹/L) and resolution of any extramedullary disease; CRi is the same with incomplete recovery of counts.

Dose Modifications

• A dose that has been reduced because of treatment-related toxicity is not re-escalated.
• Blood counts at Day 1 of a cycle: if neutrophils (at least 1 × 10⁹/L before treatment) or platelets (at least 50 × 10⁹/L before treatment) fall, the next cycle is interrupted until they recover to those levels. If counts were lower before treatment, the next cycle is interrupted until counts recover to at least the baseline of the prior cycle, or reach 1 × 10⁹/L (neutrophils) and 50 × 10⁹/L (platelets), or until disease is stable or improved and the fall is attributed to the underlying disease. Doses on Days 8 and 15 need not be interrupted for neutropenia or thrombocytopenia, but interruptions within a cycle are recommended for non-haematological toxicities.
• VOD/SOS or other severe liver toxicity: discontinue permanently.
• Total bilirubin above 1.5 times the upper limit of normal (ULN) and AST/ALT above 2.5 times ULN: interrupt until recovery to 1.5 × ULN or less and 2.5 × ULN or less before each dose, unless due to Gilbert’s disease or haemolysis; discontinue permanently if they do not recover.
• Infusion-related reaction: interrupt the infusion and institute medical management; consider stopping the infusion or giving steroids and antihistamines. Discontinue permanently for severe or life-threatening reactions.
• Other treatment-related non-haematological toxicity of grade 2 or higher: interrupt until recovery to grade 1 or the pre-treatment grade before each dose.
• Length of interruption: under 7 days within a cycle, interrupt the next dose; 7 days or more, omit the next dose in the cycle; 14 days or more, once recovered decrease the total dose by 25% for the next cycle, then to 2 doses per cycle if more modification is needed, and discontinue if that is not tolerated; more than 28 days, consider permanent discontinuation.

Special Populations

• Elderly: no adjustment of the starting dose.
• Hepatic impairment: no adjustment of the starting dose when total bilirubin is 1.5 × ULN or less and AST/ALT 2.5 × ULN or less. Safety information is limited above those levels: dosing is interrupted until recovery before each dose, and treatment is stopped if they do not recover.
• Renal impairment: no adjustment of the starting dose in mild, moderate or severe impairment (creatinine clearance 60–89, 30–59 or 15–29 mL/min). It has not been studied in end-stage renal disease.
• Children: the regimen above applies from 1 year of age; safety and efficacy below 1 year have not been established.

Hepatotoxicity, Including VOD/SOS

• Hepatotoxicity, including severe, life-threatening and sometimes fatal VOD/SOS, was reported in patients with relapsed or refractory ALL. Besponsa significantly increased the risk of VOD/SOS above that of standard chemotherapy in this population, most markedly in patients who had a subsequent HSCT.
• After HSCT, the reported frequency of VOD/SOS was 50% or more in patients who received a conditioning regimen containing 2 alkylating agents, in patients aged 65 years or older, and in patients with serum bilirubin at or above the ULN before HSCT.
• Conditioning regimens with 2 alkylating agents should be avoided, and the benefit/risk should be carefully considered where they are likely to be unavoidable. If bilirubin is at or above the ULN before HSCT, HSCT after Besponsa should only follow careful consideration of the benefit/risk, with close monitoring for VOD/SOS.
• Other factors linked to a higher risk of VOD/SOS after HSCT are a prior HSCT, age 55 years or older, a history of liver disease and/or hepatitis before treatment, later salvage lines and a greater number of treatment cycles. Careful consideration is needed in patients who have had a prior HSCT; no patient in the studies had a transplant within the previous 4 months.
• Patients with a history of liver disease should be carefully evaluated (for example ultrasound, viral hepatitis testing) to exclude serious ongoing hepatic disease. Because of the VOD/SOS risk, 2 cycles are recommended for patients proceeding to HSCT.
• Signs and symptoms of VOD/SOS should be monitored closely in all patients, especially after HSCT. They may include raised total bilirubin, hepatomegaly (which may be painful), rapid weight gain and ascites; monitoring bilirubin alone may not identify every patient at risk. ALT, AST, total bilirubin and alkaline phosphatase should be checked before and after each dose, more often if abnormal, and closely during the first month after HSCT.
• Treatment must be permanently discontinued if VOD/SOS occurs. Severe VOD/SOS is treated according to standard medical practice.

Myelosuppression and Infections

Neutropenia, thrombocytopenia, anaemia, leukopenia, febrile neutropenia, lymphopenia and pancytopenia, some life-threatening, have been reported, with complications such as infections and bleeding. Complete blood counts should be monitored before each dose, and patients watched for signs of infection (during treatment and after HSCT), bleeding and other effects of myelosuppression. Prophylactic anti-infectives and surveillance testing should be used as appropriate. Management may need a dosing interruption, dose reduction or discontinuation.

Infusion-Related Reactions

Infusion-related reactions have been reported. Premedication with a corticosteroid, antipyretic and antihistamine is recommended, and patients should be monitored closely during and for at least 1 hour after the infusion for symptoms such as hypotension, hot flush or breathing problems. If a reaction occurs, the infusion is interrupted and treated; for severe or life-threatening reactions treatment is permanently discontinued.

Tumour Lysis Syndrome

Tumour lysis syndrome, which may be life-threatening or fatal, has been reported. For patients with a high tumour burden, premedication to reduce uric acid levels and hydration are recommended before dosing. Patients are monitored for signs and symptoms and treated according to standard medical practice.

QT Interval Prolongation

QT prolongation has been observed. Besponsa should be used with caution in patients with a history of, or predisposition to, QT prolongation, who take medicines known to prolong the QT interval, or who have electrolyte disturbances. An ECG and electrolytes should be obtained before treatment and monitored periodically.

Increased Amylase and Lipase

Increases in amylase and lipase have been reported in adults and children. They should be monitored, and potential hepatobiliary disease evaluated and treated according to standard medical practice.

Immunisation

The safety of immunisation with live viral vaccines during or after Besponsa has not been studied. Live viral vaccines are not recommended for at least 2 weeks before the start of treatment, during treatment, and until B lymphocytes have recovered after the last cycle.

Traceability

To improve traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded.

Pregnancy, Breastfeeding and Fertility

• Contraception: women of childbearing potential should avoid becoming pregnant and use effective contraception during treatment and for at least 8 months after the final dose. Men with female partners of childbearing potential should use effective contraception during treatment and for at least 5 months after the final dose.
• Pregnancy: there are no data in pregnant women. Based on non-clinical findings, inotuzumab ozogamicin can cause embryo-foetal harm, and animal studies have shown reproductive toxicity. It must not be used in pregnancy unless the benefit to the mother outweighs the risk to the foetus. Pregnant women, patients who become pregnant during treatment, and treated male partners of pregnant women must be told of the potential hazard to the foetus.
• Breastfeeding: there are no data on its presence in human milk. Women must not breastfeed during treatment and for at least 2 months after the final dose.
• Fertility: non-clinical findings suggest male and female fertility may be compromised, and there is no information in patients. Both men and women must seek advice on fertility preservation before treatment.

Sodium

Each 1 mg vial contains less than 1 mmol (23 mg) of sodium, that is, it is essentially ‘sodium-free’. Because the product may be further prepared with sodium-containing solutions, this should be counted in the total sodium given to the patient.

Effect on Driving

Besponsa has a moderate influence on the ability to drive and use machines. Patients may feel fatigue during treatment, so care is advised when driving or operating machines.

Store Besponsa in a refrigerator at 2 °C to 8 °C. Do not freeze. Keep the vial in its original carton to protect it from light. Keep the cold chain unbroken from supply to preparation. For storage after reconstitution and dilution, see Shelf Life. Each carton holds one Type I amber glass vial with a chlorobutyl rubber stopper and a crimp seal with a flip-off cap, containing 1 mg of powder.

5 years for the unopened vial. Besponsa contains no bacteriostatic preservatives. The reconstituted solution must be used immediately; if that is not possible it may be kept for up to 4 hours in a refrigerator (2–8 °C), protected from light and not frozen. The diluted solution must be used immediately or stored at room temperature (20–25 °C) or in a refrigerator (2–8 °C), protected from light and not frozen. The maximum time from reconstitution to the end of administration is 8 hours, with no more than 4 hours between reconstitution and dilution.

Prescription only (Rx). Treatment is given under the supervision of a physician experienced in cancer therapy, in a setting with full resuscitation facilities. Besponsa is an intravenous infusion and is a refrigerated (2–8 °C) product, so it is supplied under cold-chain conditions to the hospital or clinic that administers it.