Inotuzumab Ozogamicin

1. INDICATIONS AND USAGE BESPONSA is indicated for the treatment of relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients 1 year and older . BESPONSA is a CD22-directed antibody and cytotoxic drug conjugate indicated for the treatment of relapsed or refractory CD22-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients 1 year and older. ( 1 )

12.1 Mechanism of Action Inotuzumab ozogamicin is a CD22-directed antibody drug conjugate (ADC). Inotuzumab recognizes human CD22. The small molecule, N-acetyl-gamma-calicheamicin, is a cytotoxic agent that is covalently attached to the antibody via a linker. Nonclinical data suggest that the anticancer activity of inotuzumab ozogamicin is due to the binding of the ADC to CD22-expressing tumor cells, followed by internalization of the ADC-CD22 complex, and the intracellular release of N-acetyl-gamma-calicheamicin dimethylhydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl-gamma-calicheamicin dimethylhydrazide induces double-strand DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.

2. DOSAGE AND ADMINISTRATION • Administer by intravenous infusion only. (2.1) • Pre-medicate with a corticosteroid, antipyretic, and antihistamine prior to all infusions. ( 2.2 ) • Dosing regimens for Cycle 1 and subsequent cycles, depending on the response to treatment, are shown below. See full prescribing information for dosing details. ( 2 ) Day 1 Day 8 Day 15 Dosing regimen for Cycle 1 All patients: Dose 0.8 mg/m 2 0.5 mg/m 2 0.5 mg/m 2 Cycle length 21 days For patients who achieve a CR or a CRi, and/or to allow for recovery from toxicity, the cycle length may be extended up to 28 days (i.e., 7-day treatment-free interval starting on Day 21). Dosing regimen for subsequent cycles depending on response to treatment Patients who have achieved a CR or CRi: Dose 0.5 mg/m 2 0.5 mg/m 2 0.5 mg/m 2 Cycle length 28 days Patients who have not achieved a CR or CRi: Dose 0.8 mg/m 2 0.5 mg/m 2 0.5 mg/m 2 Cycle length 28 days • See full prescribing information for instructions on reconstitution of lyophilized powder, and preparation and administration of reconstituted drug. ( 2.4 ) 2.1 Recommended Dosage • Pre-medicate before each dose [see Dosage and Administration (2.2) ] . • Administer by intravenous infusion only. • For the first cycle, the recommended total dose of BESPONSA for all patients is 1.8 mg/m 2 per cycle, administered as 3 divided doses on Day 1 (0.8 mg/m 2 ), Day 8 (0.5 mg/m 2 ), and Day 15 (0.5 mg/m 2 ). Cycle 1 is 3 weeks in duration, but may be extended to 4 weeks if the patient achieves a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), and/or to allow recovery from toxicity. • For subsequent cycles: • In patients who achieve a CR or CRi, the recommended total dose of BESPONSA is 1.5 mg/m 2 per cycle, administered as 3 divided doses on Day 1 (0.5 mg/m 2 ), Day 8 (0.5 mg/m 2 ), and Day 15 (0.5 mg/m 2 ). Subsequent cycles are 4 weeks in duration. OR • In patients who do not achieve a CR or CRi, the recommended total dose of BESPONSA is 1.8 mg/m 2 per cycle given as 3 divided doses on Day 1 (0.8 mg/m 2 ), Day 8 (0.5 mg/m 2 ), and Day 15 (0.5 mg/m 2 ). Subsequent cycles are 4 weeks in duration. Patients who do not achieve a CR or CRi within 3 cycles should discontinue treatment. • For patients proceeding to hematopoietic stem cell transplant (HSCT), the recommended duration of treatment with BESPONSA is 2 cycles. A third cycle may be considered for those patients who do not achieve CR or CRi and minimal residual disease (MRD) negativity after 2 cycles [see Warnings and Precautions (5.1) ] . • For patients not proceeding to HSCT, additional cycles of treatment, up to a maximum of 6 cycles, may be administered. Table 1 shows the recommended dosing regimens. Table 1. Dosing Regimen for Cycle 1 and Subsequent Cycles Depending on Response to Treatment Abbreviations: CR=complete remission; CRi=complete remission with incomplete hematologic recovery. Day 1 Day 8 +/- 2 days (maintain minimum of 6 days between doses). Day 15 Dosing regimen for Cycle 1 All patients: Dose Dose is based on the patient's body surface area (m 2 ). 0.8 mg/m 2 0.5 mg/m 2 0.5 mg/m 2 Cycle length 21 days For patients who achieve a CR or a CRi, and/or to allow for recovery from toxicity, the cycle length may be extended up to 28 days (i.e., 7-day treatment-free interval starting on Day 21). Dosing regimen for subsequent cycles depending on response to treatment Patients who have achieved a CR CR is defined as < 5% blasts in the bone marrow and the absence of peripheral blood leukemic blasts, full recovery of peripheral blood counts (platelets ≥ 100 × 10 9 /L and absolute neutrophil counts [ANC] ≥ 1 × 10 9 /L) and resolution of any extramedullary disease. or CRi CRi is defined as < 5% blasts in the bone marrow and the absence of peripheral blood leukemic blasts, incomplete recovery of peripheral blood counts (platelets < 100 × 10 9 /L and/or ANC < 1 × 10 9 /L) and resolution of any extramedullary disease. : Dose 0.5

6. ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Hepatotoxicity, including hepatic VOD (also known as SOS) [see Warnings and Precautions (5.1) ] • Increased risk of post-transplant non-relapse mortality [see Warnings and Precautions (5.2) ] • Myelosuppression [see Warnings and Precautions (5.3) ] • Infusion related reactions [see Warnings and Precautions (5.4) ] • QT interval prolongation [see Warnings and Precautions (5.5) ] The most common (≥ 20%) adverse reactions, including laboratory abnormalities, in adult and pediatric patients are thrombocytopenia, pyrexia, neutropenia, infection, anemia, vomiting, leukopenia, hemorrhage, fatigue, nausea, febrile neutropenia, headache, transaminases increased, abdominal pain, and gamma-glutamyltransferase increased, and hyperbilirubinemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Relapsed or Refractory B-cell Precursor ALL Adult Patients The safety of BESPONSA was evaluated in adult patients with relapsed or refractory B-cell precursor ALL in the INO-VATE ALL trial. The study was a randomized clinical study of BESPONSA (n=164) versus Investigator’s choice of chemotherapy (fludarabine + cytarabine + granulocyte colony-stimulating factor [FLAG], mitoxantrone + cytarabine [MXN/Ara-C], or high dose cytarabine [HIDAC]) (n=143) [see Clinical Studies (14) ] . Of the 164 patients who received BESPONSA, the median age was 47 years (range: 18–78 years), 56% were male, 68% had received 1 prior treatment regimen for ALL, 31% had received 2 prior treatment regimens for ALL, 68% were White, 19% were Asian, and 2% were Black. In patients who received BESPONSA, the median duration of treatment was 8.9 weeks (range: 0.1–26.4 weeks), with a median of 3 treatment cycles started in each patient. In patients who received Investigator's choice of chemotherapy, the median duration of treatment was 0.9 weeks (range: 0.1–15.6 weeks), with a median of 1 treatment cycle started in each patient. In patients who received BESPONSA, the most common (≥ 20%) adverse reactions were thrombocytopenia, neutropenia, infection, anemia, leukopenia, fatigue, hemorrhage, pyrexia, nausea, headache, febrile neutropenia, transaminases increased, abdominal pain, gamma-glutamyltransferase increased, and hyperbilirubinemia. In patients who received BESPONSA, the most common (≥ 2%) serious adverse reactions were infection, febrile neutropenia, hemorrhage, abdominal pain, pyrexia, VOD, and fatigue. In patients who received BESPONSA, the most common (≥ 2%) adverse reactions reported as the reason for permanent discontinuation were infection (6%), thrombocytopenia (2%), hyperbilirubinemia (2%), transaminases increased (2%), and hemorrhage (2%); the most common (≥ 5%) adverse reactions reported as the reason for dosing interruption were neutropenia (17%), infection (10%), thrombocytopenia (10%), transaminases increased (6%), and febrile neutropenia (5%); and the most common (≥ 1%) adverse reactions reported as the reason for dose reduction were neutropenia (1%), thrombocytopenia (1%), and transaminases increased (1%). VOD was reported in 23/164 patients (14%) who received BESPONSA during or following treatment or following a HSCT after completion of treatment [see Warnings and Precautions (5.1) ]. Table 7 shows the adverse reactions with ≥ 10% incidence reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy. Table 7. Adverse Reactions With ≥ 10% Incidence Only adverse reactions with ≥ 10% incidence in the BESPONSA arm are inclu

5. WARNINGS AND PRECAUTIONS • Myelosuppression: Monitor complete blood counts; for signs and symptoms of infection; bleeding/hemorrhage; or other effects of myelosuppression during treatment; manage appropriately. ( 5.3 ) • Infusion related reactions: Monitor for infusion related reactions during and for at least 1 hour after infusion ends. ( 5.4 ) • QT interval prolongation: Obtain electrocardiograms (ECGs) and electrolytes at baseline and monitor during treatment. Monitor more frequently when using concomitant mediations known to prolong QT interval. ( 5.5 ) • Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 ) 5.1 Hepatotoxicity, Including Hepatic Veno-occlusive Disease (VOD) (also known as Sinusoidal Obstruction Syndrome) BESPONSA can cause hepatotoxicity, including VOD. In adult patients in the INO-VATE ALL trial, hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic VOD occurred in 23/164 patients (14%) in the BESPONSA arm during or following treatment or following a HSCT after completion of treatment. VOD occurred up to 56 days after the final dose during treatment or during follow-up without an intervening HSCT. The median time from subsequent HSCT to onset of VOD was 15 days (range: 3-57 days). In the BESPONSA arm, among the 79 patients who proceeded to a subsequent HSCT, VOD occurred in 18/79 patients (23%), and among all 164 patients treated, VOD occurred in 5/164 patients (3%) during study therapy or in follow-up without an intervening HSCT. The risk of VOD was greater in patients who underwent HSCT after BESPONSA treatment; use of HSCT conditioning regimens containing 2 alkylating agents (e.g., busulfan in combination with other alkylating agents) and last total bilirubin level greater than or equal to the ULN before HSCT are significantly associated with an increased risk of VOD. Other risk factors for VOD in patients treated with BESPONSA included ongoing or prior liver disease, prior HSCT, increased age, later salvage lines, and a greater number of BESPONSA treatment cycles. Patients who have experienced prior VOD or have serious ongoing hepatic liver disease (e.g., cirrhosis, nodular regenerative hyperplasia, active hepatitis) are at an increased risk for worsening of liver disease, including developing VOD, following treatment with BESPONSA. In Study WI203581 (ITCC-059) VOD occurred in 8/53 (15%) of pediatric patients treated with single agent BESPONSA. Among the 26 pediatric patients who underwent HSCT, VOD occurred in 5 (19%) patients [see Adverse Reactions (6.1) ] . Monitor closely for signs and symptoms of VOD including elevations in total bilirubin, hepatomegaly (which may be painful), rapid weight gain, and ascites. Due to the risk of VOD, for patients proceeding to HSCT, the recommended duration of treatment with BESPONSA is 2 cycles; a third cycle may be considered for those patients who do not achieve a CR or CRi and MRD negativity after 2 cycles [see Dosage and Administration (2.1) ] . For patients who proceed to HSCT, monitor liver tests at least weekly during the first month post-HSCT, then less frequently thereafter, according to standard medical practice. In adult patients in the INO-VATE ALL trial, increases in liver test abnormalities occurred. Grade 3 or 4 AST, ALT, and total bilirubin abnormal liver tests occurred in 7/160 (4%), 7/161 (4%), and 8/161 patients (5%), respectively. In pediatric patients in Study WI203581 (ITCC-059), liver test abnormalities occurred, with Grade 3 or 4 increases in AST, ALT, and blood bilirubin in 11/53 (21%), 11/53 (21%), and 5/53 (9%) of patients, respectively [see Adverse Reactions (6.1) ] . In all patients, monitor liver tests, including ALT, AST, total bilirubin, and alkaline phosphatase, prior to and following each dose of BESPONSA. Based on elevations of liver tests withhold, reduce dose, or permanently disco

4. CONTRAINDICATIONS None. None ( 4 )