BESPONSA

Inotuzumab ozogamicin is a CD22-directed antibody and cytotoxic-drug conjugate (ADC) consisting of 3 components: 1) the recombinant humanized immunoglobulin class G subtype 4 (IgG4) kappa antibody inotuzumab, specific for human CD22, 2) N-acetyl-gamma-calicheamicin that causes double-stranded DNA breaks, and 3) an acid-cleavable linker composed of the condensation product of 4-(4'-acetylphenoxy)-butanoic acid (AcBut) and 3-methyl-3-mercaptobutane hydrazide (known as dimethylhydrazide) that covalently attaches N-acetyl-gamma-calicheamicin to inotuzumab. Inotuzumab ozogamicin has an approximate molecular weight of 160 kDa. The average number of calicheamicin derivative molecules conjugated to each inotuzumab molecule is approximately 6 with a distribution from 2–8. Inotuzumab ozogamicin is produced by chemical conjugation of the antibody and small molecule components. The antibody is produced by mammalian (Chinese hamster ovary) cells, and the semisynthetic calicheamicin derivative is produced by microbial fermentation followed by synthetic modification. BESPONSA (inotuzumab ozogamicin) for injection is supplied as a sterile, white to off-white, preservative-free, lyophilized powder for intravenous administration. Each single-dose vial delivers 0.9 mg inotuzumab ozogamicin. Inactive ingredients are polysorbate 80 (0.36 mg), sodium chloride (2.16 mg), sucrose (180 mg), and tromethamine (8.64 mg). After reconstitution with 4 mL of Sterile Water for Injection, USP, the final concentration is 0.25 mg/mL of inotuzumab ozogamicin with a deliverable volume of 3.6 mL (0.9 mg) and a pH of approximately 8.0. Chemical Structure

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 )

• 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 mg/m 2 0.5 mg/m 2 0.5 mg/m 2 Cycle length 28 days 7-day treatment-free interval starting on Day 21. 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 2.2 Recommended Pre-medications and Cytoreduction • Premedication with a corticosteroid, antipyretic, and antihistamine is recommended prior to dosing. Patients should be observed during and for at least 1 hour after the end of infusion for symptoms of infusion related reactions [see Warnings and Precautions (5.4) ] . • For patients with circulating lymphoblasts, cytoreduction with a combination of hydroxyurea, steroids, and/or vincristine to a peripheral blast count of less than or equal to 10,000/mm 3 is recommended prior to the first dose. 2.3 Dosage Modifications for Adverse Reactions Modify the dose of BESPONSA for toxicities (see Tables 2–4). BESPONSA doses within a treatment cycle (i.e., Days 8 and/or 15) do not need to be interrupted due to neutropenia or thrombocytopenia, but dosing interruptions within a cycle are recommended for non-hematologic toxicities. If the dose is reduced due to BESPONSA-related toxicity, the dose must not be re-escalated. Table 2. BESPONSA Dosage Modifications for Hematologic Toxicities [see Warnings and Precautions (5.3) ] Criteria BESPONSA Dosage Modification(s) Abbreviation: ANC=absolute neutrophil count. If prior to BESPONSA treatment ANC was greater than or equal to 1 × 10 9 /L If ANC decreases, then interrupt the next cycle of treatment until recovery of ANC to greater than or equal to 1 × 10 9 /L. Discontinue BESPONSA if low ANC persists for greater than 28 days and is suspected to be related to BESPONSA. If prior to BESPONSA treatment platelet count was greater than or equal to 50 × 10 9 /L Platelet count used for dosing should be independent of blood transfusion. If platelet count decreases, then interrupt the next cycle of treatment until platelet count recovers to greater than or equal to 50 × 10 9 /L . Discontinue BESPONSA if low platelet count persists for greater than 28 days and is suspected to be related to BESPONSA. If prior to BESPONSA treatment ANC was less than 1 × 10 9 /L and/or platelet count was less than 50 × 10 9 /L If ANC or platelet count decreases, then interrupt the next cycle of treatment until at least one of the following occurs: - ANC and platelet counts recover to at least baseline levels for the prior cycle, or - ANC recovers to greater than or equal to 1 × 10 9 /L and platelet count recovers to greater than or equal to 50 × 10 9 /L , or - Stable or improved disease (based on most recent bone marrow assessment) and the ANC and platelet count decrease is considered to be due to the underlying disease (not considered to be BESPONSA-related toxicity). Table 3. BESPONSA Dosage Modifications for Non-hematologic Toxicities Non-hematologic Toxicity Dosage Modification(s) Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal; VOD=veno‑occlusive disease. VOD or other severe liver toxicity Permanently discontinue treatment [see Warnings and Precautions (5.1) ] . Total bilirubin greater than 1.5 × ULN and AST / ALT greater than 2.5 × ULN Interrupt dosing until recovery of total bilirubin to less than or equal to 1.5 × ULN and AST/ALT to less than or equal to 2.5 × ULN prior to each dose unless due to Gilbert's syndrome or hemolysis. Permanently discontinue treatment if total bilirubin does not recover to less than or equal to 1.5 × ULN or AST/ALT does not recover to less than or equal to 2.5 × ULN [see Warnings and Precautions (5.1) ] . Infusion related reaction Interrupt the infusion and institute appropriate medical management. Depending on the severity of the infusion related reaction, consider discontinuation of the infusion or administration of steroids and antihistamines. For severe or life-threatening infusion reactions, permanently discontinue treatment [see Warnings and Precautions (5.4) ] . Non-hematologic toxicity greater than or equal to Grade 2 Severity grade according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. Interrupt treatment until recovery to Grade 1 or pre-treatment grade levels prior to each dose. Table 4. BESPONSA Dosage Modifications Depending on Duration of Dosing Interruption Due to Non-Hematologic Toxicity Toxicities Duration of Dose Interruption Due to Toxicity Dosage Modification(s) Less than 7 days (within a cycle) Interrupt the next dose (maintain a minimum of 6 days between doses). Greater than or equal to 7 days Omit the next dose within the cycle. Greater than or equal to 14 days Once adequate recovery is achieved, decrease the total dose by 25% for the subsequent cycle. If further dose modification is required, then reduce the number of doses to 2 per cycle for subsequent cycles. If a 25% decrease in the total dose followed by a decrease to 2 doses per cycle is not tolerated, then permanently discontinue treatment. Greater than 28 days Consider permanent discontinuation of treatment. 2.4 Instructions for Reconstitution, Dilution, and Administration Protect the reconstituted and diluted BESPONSA solutions from light. Do not freeze the reconstituted or diluted solution. The maximum time from reconstitution through the end of administration should be less than or equal to 8 hours, with less than or equal to 4 hours between reconstitution and dilution. Reconstitution : • BESPONSA is a hazardous drug. Follow applicable special handling and disposal procedures. 1 • Calculate the dose (mg) and number of vial(s) of BESPONSA required. • Reconstitute each vial with 4 mL of Sterile Water for Injection, USP, to obtain a concentration of 0.25 mg/mL of BESPONSA that delivers 3.6 mL (0.9 mg). • Gently swirl the vial to aid dissolution. DO NOT SHAKE . • Inspect the reconstituted solution for particulates and discoloration. The reconstituted solution should be clear to opalescent, colorless to slightly yellow, and essentially free of visible foreign matter. • See Table 6 for storage times and conditions for the reconstituted solution. Dilution : • Withdraw the required volume of the reconstituted solution from the vial(s) needed to obtain the appropriate dose according to the patient’s body surface area. Discard any unused reconstituted BESPONSA solution left in the vial. • Dilute the reconstituted BESPONSA solution in 0.9% Sodium Chloride Injection, USP, in the appropriate infusion container per Table 5: Table 5. Infusion Container Information Infusion Bag Administration Syringe Administration • For calculated doses greater than or equal to 0.5 mg • Ensure a final prepared concentration of 0.01 mg/mL to 0.1 mg/mL in a total volume of 50 mL • For calculated doses less than 0.5 mg • Ensure a final prepared concentration of 0.025 mg/mL to 0.1 mg/mL in a total volume between 2 mL to 50 mL • Gently invert the infusion container to mix the diluted solution. DO NOT SHAKE . • PROTECT FROM LIGHT. • See Table 6 for storage times and conditions for the diluted solution. Administration : • See Table 6 for storage times and conditions for prior to and during administration of the diluted solution. • For syringe infusions, a syringe pump and micro-bore IV tubing must be used. • Filtration of the diluted solution is not required. However, if the diluted solution is filtered, polyethersulfone (PES)-, polyvinylidene fluoride (PVDF),- or hydrophilic polysulfone (HPS) -based filters are recommended. Do not use filters made of nylon or mixed cellulose ester (MCE). • Infuse the diluted solution as an intravenous infusion over one hour. Flush the intravenous infusion line with 0.9% Sodium Chloride Injection, USP, to ensure the complete dose is administered. Do not mix BESPONSA or administer as an infusion with other medicinal products. Table 6 shows the storage times and conditions for reconstitution, dilution, and administration of BESPONSA. Table 6. Storage Times and Conditions for Reconstituted and Diluted BESPONSA Solution Storage Time and Conditions Maximum time from reconstitution through end of administration less than or equal to 8 hours with less than or equal to 4 hours between reconstitution and dilution. Reconstituted Solution • BESPONSA contains no bacteriostatic preservatives. Use reconstituted solution immediately or store refrigerated at (2°C-8°C; 36°F-46°F) for up to 4 hours. • PROTECT FROM LIGHT. DO NOT FREEZE. Diluted Solution • Use diluted solution immediately or store at room temperature (20°C-25°C; 68°F-77°F) or refrigerated (2°C-8°C; 36°F-46°F) for up to 6 hours. • If the diluted solution is refrigerated (2°C-8°C; 36°F-46°F), allow it to equilibrate at room temperature (20°C-25°C; 68°F-77°F) for approximately 1 hour prior to administration. • Administer diluted solution within 8 hours of reconstitution including the 1 hour equilibration and 1 hour infusion. • PROTECT FROM LIGHT. DO NOT FREEZE.

None. None ( 4 )

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 included. in Adult Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator's Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC) Body System Adverse Reaction BESPONSA (N=164) FLAG, MXN/Ara-C, or HIDAC (N=143 19 patients randomized to FLAG, MXN/Ara-C, or HIDAC did not receive treatment. ) All Grades ≥ Grade 3 All Grades ≥ Grade 3 % % % % Adverse reactions included treatment-emergent all-causality events that commenced on or after Cycle 1 Day 1 within 42 days after the final dose of BESPONSA, but prior to the start of a new anticancer treatment (including HSCT). Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 18.1. Severity grade of adverse reactions were according to NCI CTCAE version 3.0. Abbreviations: ALL=acute lymphoblastic leukemia; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; HIDAC=high dose cytarabine; HSCT=hematopoietic stem cell transplant; MXN/Ara-C=mitoxantrone + cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events. Infections Infection Infection includes any reported preferred terms for BESPONSA retrieved in the System Organ Class Infections and infestations. 48 28 76 54 Blood and lymphatic system disorders Thrombocytopenia Thrombocytopenia includes the following reported preferred terms: Platelet count decreased and Thrombocytopenia. 51 42 61 59 Neutropenia Neutropenia includes the following reported preferred terms: Neutropenia and Neutrophil count decreased. 49 48 45 43 Anemia Anemia includes the following reported preferred terms: Anemia and Hemoglobin decreased. 36 24 59 47 Leukopenia Leukopenia includes the following reported preferred terms: Leukopenia, Monocytopenia, and White blood cell count decreased. 35 33 43 42 Febrile neutropenia 26 26 53 53 Lymphopenia Lymphopenia includes the following reported preferred terms: B-lymphocyte count decreased, Lymphocyte count decreased, and Lymphopenia. 18 16 27 26 Metabolism and nutrition disorders Decreased appetite 12 1 13 2 Nervous system disorders Headache Headache includes the following reported preferred terms: Headache, Migraine, and Sinus headache. 28 2 27 1 Vascular disorders Hemorrhage Hemorrhage includes reported preferred terms for BESPONSA retrieved in the Standard MedDRA Query (narrow) for Hemorrhage terms (excluding laboratory terms), resulting in the following preferred terms: Conjunctival hemorrhage, Contusion, Ecchymosis, Epistaxis, Eyelid bleeding, Gastrointestinal hemorrhage, Gastritis hemorrhagic, Gingival bleeding, Hematemesis, Hematochezia, Hematotympanum, Hematuria, Hemorrhage intracranial, Hemorrhage subcutaneous, Hemorrhoidal hemorrhage, Intra-abdominal hemorrhage, Lip hemorrhage, Lower gastrointestinal hemorrhage, Mesenteric hemorrhage, Metrorrhagia, Mouth hemorrhage, Muscle hemorrhage, Oral mucosa hematoma, Petechiae, Post-procedural hematoma, Rectal hemorrhage, Shock hemorrhagic, Subcutaneous hematoma, Subdural hematoma, Upper gastrointestinal hemorrhage, and Vaginal hemorrhage. 33 5 28 5 Gastrointestinal disorders Nausea 31 2 46 0 Abdominal pain Abdominal pain includes the following reported preferred terms: Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Esophageal pain, and Hepatic pain. 23 3 23 1 Diarrhea 17 1 38 1 Constipation 16 0 24 0 Vomiting 15 1 24 0 Stomatitis Stomatitis includes the following reported preferred terms: Aphthous ulcer, Mucosal inflammation, Mouth ulceration, Oral pain, Oropharyngeal pain, and Stomatitis. 13 2 26 3 Hepatobiliary disorders Hyperbilirubinemia 21 5 17 6 General disorders and administration site conditions Fatigue Fatigue includes the following reported preferred terms: Asthenia and Fatigue. 35 5 25 3 Pyrexia 32 3 42 6 Chills 11 0 11 0 Investigations Transaminases increased Transaminases increased includes the following reported preferred terms: Aspartate aminotransferase increased, Alanine aminotransferase increased, Hepatocellular injury, and Hypertransaminasemia. 26 7 13 5 Gamma-glutamyltransferase increased 21 10 8 4 Alkaline phosphatase increased 13 2 7 0 Additional adverse reactions (all grades) that were reported in less than 10% of patients treated with BESPONSA included: lipase increased (9%), abdominal distension (6%), amylase increased (5%), hyperuricemia (4%), ascites (4%), infusion related reaction (2%; includes the following: hypersensitivity and infusion related reaction), pancytopenia (2%; includes the following: bone marrow failure, febrile bone marrow aplasia, and pancytopenia), tumor lysis syndrome (2%), and electrocardiogram QT prolonged (1%). Table 8 shows the clinically important laboratory abnormalities reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy. Table 8. Laboratory Abnormalities in Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator's Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC) BESPONSA FLAG, MXN/Ara-C, or HIDAC All Grades Grade 3/4 All Grades Grade 3/4 Laboratory Abnormality Laboratory abnormalities were summarized up to the end of treatment + 42 days but prior to the start of a new anti-cancer therapy. N % % N % % Severity grade of laboratory abnormalities according to NCI CTCAE version 3.0. Abbreviations: ALL=acute lymphoblastic leukemia; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; GGT=gamma-glutamyltransferase; HIDAC=high dose cytarabine; MXN/Ara-C=mitoxantrone + cytarabine; N=number of patients; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events. Hematology Platelet count decreased 161 98 76 142 100 99 Hemoglobin decreased 161 94 40 142 100 70 Leukocytes decreased 161 95 82 142 99 98 Neutrophil count decreased 160 94 86 130 93 88 Lymphocytes (absolute) decreased 160 93 71 127 97 91 Chemistry GGT increased 148 67 18 111 68 17 AST increased 160 71 4 134 38 4 ALP increased 158 57 1 133 52 3 ALT increased 161 49 4 137 46 4 Blood bilirubin increased 161 36 5 138 35 6 Lipase increased 139 32 13 90 20 2 Hyperuricemia 158 16 3 122 11 0 Amylase increased 143 15 2 102 9 1 Pediatric Patients The safety of BESPONSA in pediatric patients 1 year and older with relapsed or refractory CD22-positive B-cell precursor ALL was evaluated in a multicenter, single-arm, open-label study (ITCC-059) [see Clinical Studies (14) ] . Patients (n=53) received the recommended dosage of BESPONSA [see Dosage and Administration (2.1) ] or BESPONSA at an initial dose of 1.4 mg/m 2 /cycle (approximately 0.78 times the recommended initial dosage). Patients received BESPONSA for a median of 2 (range: 1-4) cycles. The median age of patients who received BESPONSA was 9 years (range: 1-17), with 68% male. Serious adverse reactions occurred in 62% of patients who received BESPONSA. Serious adverse reactions in > 2% of patients included infection (21%), febrile neutropenia (17%), VOD (15%), hemorrhage (4%), pyrexia (6%) and multiorgan failure (2%). Fatal adverse reactions occurred in 8% of patients who received BESPONSA, including multiorgan failure, lung infection, sepsis, and encephalopathy. Permanent discontinuation of BESPONSA due to an adverse reaction occurred in 21% of patients. Adverse reactions which resulted in permanent discontinuation of BESPONSA in 2 or more patients included ALT increased and platelet count decreased. Dosage interruptions of BESPONSA due to an adverse reaction occurred in 11% of patients. Adverse reactions which required dosage interruption of BESPONSA in 6 patients included increased transaminases, febrile neutropenia, and headache. The most common adverse reactions (≥ 20%), including laboratory abnormalities, were thrombocytopenia, pyrexia, anemia, vomiting, infection, hemorrhage, neutropenia, nausea, leukopenia, febrile neutropenia, increased transaminases, abdominal pain, and headache. Table 9 summarizes the adverse reactions in ITCC-059. Table 9. Adverse Reactions (≥ 5%) in Pediatric Patients (N=53) With CD22-Positive Relapsed or Refractory ALL in Study WI203581 (ITCC-059) Severity grade of adverse reactions were according to NCI CTCAE version 4.03. Body System Adverse Reaction BESPONSA Monotherapy (N=53) All Grades ≥ Grade 3 % % General disorders and administration site conditions Pyrexia 49 4 Edema Includes other related terms. 19 0 Fatigue 17 0 Pain 15 2 Chills 8 0 Blood and lymphatic system disorders Anemia 45 38 Febrile neutropenia 28 28 Gastrointestinal disorders Vomiting 45 2 Nausea 32 0 Abdominal pain 25 2 Constipation 19 2 Stomatitis 17 6 Diarrhea 11 0 Infections and infestations Infection Infection includes any reported preferred terms for system organ class infections and infestations resulting in the following preferred terms: Acinetobacter bacteremia, bacteremia, candida infection, Cytomegalovirus infection, device related infection, device related sepsis, encephalitis, infectious enterocolitis, fungal infection, herpes virus infection, herpes zoster, influenza, kidney infection, mucosal infection, otitis media, paronychia, pneumonia, pneumonia fungal, respiratory tract infection, rhinitis, sepsis, sinusitis, skin infection, stoma site infection, upper respiratory tract infection, urinary tract inflammation, urinary tract infection, vaginal infection. 43 23 Vascular disorders Hemorrhage Hemorrhage includes any reported PT terms within the hemorrhage terms (excl laboratory terms) (SMQ) narrow, resulting in the following preferred terms: catheter site hemorrhage, diarrhea hemorrhagic, epistaxis, gingival bleeding, hematemesis, hematoma, hematuria, hemoptysis, hemorrhage intracranial, hemorrhoidal hemorrhage, lip hemorrhage, mouth hemorrhage, oral blood blister, petechiae, purpura, thrombotic thrombocytopenic purpura, and upper gastrointestinal hemorrhage. 42 6 Hypotension 6 4 Nervous system disorders Headache 21 0 Skin and subcutaneous tissue disorders Rash 19 4 Pruritis 9 0 Hyperhidrosis 6 0 Musculoskeletal and connective tissue disorders Pain in extremity 19 2 Back pain 6 0 Neck pain 6 0 Muscular weakness 6 0 Respiratory, thoracic and mediastinal disorders Cough 17 0 Dyspnea 8 2 Hypoxia 8 4 Hepatobiliary disorders Veno-occlusive disease 15 13 Hyperbilirubinemia 9 8 Metabolism and nutrition disorders Decreased appetite 11 4 Tumor lysis syndrome 11 11 Investigations Weight increased 8 2 Injury, poisoning and procedural complications Infusion related reaction Infusion related reaction includes the following preferred terms: infusion-related reaction and hypersensitivity. 8 0 Cardiac disorders Sinus tachycardia 6 2 Psychiatric disorders Anxiety 6 0 Table 10 summarizes select laboratory abnormalities in pediatric patients with CD22-positive relapsed/refractory ALL after receiving BESPONSA monotherapy in Study WI203581 (ITCC-059). Table 10. Select Laboratory Abnormalities in Pediatric Patients with CD22-positive Relapsed/Refractory ALL after receiving BESPONSA Monotherapy in Study WI203581 (ITCC-059) Severity grade of laboratory abnormalities according to NCI CTCAE version 4.03. Abbreviations: N= number of subjects with valid post-baseline assessment; NCI CTCAE=National Cancer Institute Common Toxicity Criteria for Adverse Events. Laboratory Abnormality BESPONSA Monotherapy All Grades Grade 3/4 N % % Hematology Platelet count decreased 53 100 85 Neutrophil count decreased 53 98 96 White blood cell decreased 53 98 89 Hemoglobin decreased 53 96 42 Lymphocyte count decreased 52 87 73 Chemistry AST increased 53 87 21 ALT increased 53 83 21 GGT increased 33 79 27 Blood bilirubin increased 53 30 9 ALP increased 53 28 0 Lipase increased 48 23 4 Serum amylase increased 49 14 0

Drugs That Prolong the QT Interval Concomitant use of BESPONSA with drugs known to prolong the QT interval or induce Torsades de Pointes may increase the risk of a clinically significant QTc interval prolongation [see Clinical Pharmacology (12.2) ] . Discontinue or use alternative concomitant drugs that do not prolong QT/QTc interval while the patient is using BESPONSA. When it is not feasible to avoid concomitant use of drugs known to prolong QT/QTc, obtain ECGs and electrolytes prior to the start of treatment, after initiation of any drug known to prolong QTc, and periodically monitor as clinically indicated during treatment [see Warnings and Precautions (5.5) ] .