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 )

3. DOSAGE FORMS AND STRENGTHS For injection: 0.9 mg as a white to off-white lyophilized powder in a single-dose vial for reconstitution and further dilution. For injection: 0.9 mg lyophilized powder in a single-dose vial for reconstitution and further dilution. ( 3 )

4. CONTRAINDICATIONS None. None ( 4 )

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 discontinue BESPONSA [see Dosage and Administration (2.3) ] .

5.2 Increased Risk of Post-Transplant Non-Relapse Mortality In adult patients in the INO-VATE ALL trial, a higher post-HSCT non-relapse mortality rate was observed in patients receiving BESPONSA compared to the Investigator's choice of chemotherapy arm, resulting in a higher Day 100 post-HSCT mortality rate. Overall, 79/164 patients (48%) in the BESPONSA arm and 35/162 patients (22%) in the Investigator's choice of chemotherapy arm had a follow-up HSCT. The post-HSCT non-relapse mortality rate was 31/79 (39%) and 8/35 (23%) in the BESPONSA arm compared to the Investigator's choice of chemotherapy arm, respectively. In the BESPONSA arm, the most common causes of post-HSCT non-relapse mortality included VOD and infections. Five of the 18 VOD events that occurred post-HSCT were fatal. In the BESPONSA arm, among patients with ongoing VOD at time of death, 6 patients died due to multiorgan failure (MOF) or infection (3 patients died due to MOF, 2 patients died due to infection, and 1 patient died due to MOF and infection). In pediatric patients in Study WI203581 (ITCC-059), 26/53 patients (49%) had a follow-up HSCT. The post-HSCT non-relapse mortality rate was 7/26 (27%). Monitor for toxicities post-HSCT, including signs and symptoms of infection and VOD [see Warnings and Precautions (5.1 , 5.3) ] .

5.3 Myelosuppression BESPONSA can cause myelosuppression, including thrombocytopenia and neutropenia [see Adverse Reactions (6.1) ] . In adult patients in the INO-VATE ALL trial, thrombocytopenia and neutropenia occurred in 83/164 patients (51%) and 81/164 patients (49%), respectively. Grade 3 thrombocytopenia and neutropenia occurred in 23/164 patients (14%) and 33/164 patients (20%), respectively. Grade 4 thrombocytopenia and neutropenia occurred in 46/164 patients (28%) and 45/164 patients (27%), respectively. Febrile neutropenia, which may be life-threatening, occurred in 43/164 patients (26%). For patients who were in CR or CRi at the end of treatment, the recovery of platelet counts to > 50,000/mm 3 was later than 45 days after the final dose in 15/164 patients (9%) who received BESPONSA and 3/162 patients (2%) who received Investigator's choice of chemotherapy. Complications associated with myelosuppression (including infections and bleeding/hemorrhage) occurred in patients receiving BESPONSA [see Adverse Reactions (6.1) ] . Infections, including serious infections, some of which were life-threatening or fatal, occurred in 79/164 patients (48%). Fatal infections, including pneumonia, neutropenic sepsis, sepsis, septic shock, and pseudomonal sepsis, occurred in 8/164 patients (5%). Bacterial, viral, and fungal infections occurred. Hemorrhage occurred in 54/164 patients (33%). Grade 3 or 4 hemorrhage occurred in 8/164 patients (5%), including a fatality in 1/164 patients (1%) (intra-abdominal hemorrhage). The most common type of hemorrhage was epistaxis which occurred in 24/164 patients (15%). In pediatric patients in Study WI203581 (ITCC-059), Grade 3 or 4 thrombocytopenia occurred in 24/53 (45%) patients. Grade 3 or 4 neutropenia occurred in 21/53 (40%) patients. Infections occurred in 23/53 (43%) patients, and hemorrhage occurred in 22/53 (42%) patients. The most common types of hemorrhage were hematoma in 8/53 (15%), mouth hemorrhage in 6/53 (11%), and epistaxis in 6/53 (11%) patients [see Adverse Reactions (6.1) ] . Monitor complete blood counts prior to each dose of BESPONSA and monitor for signs and symptoms of infection, bleeding/hemorrhage, or other effects of myelosuppression during treatment with BESPONSA. As appropriate, administer prophylactic anti-infectives and employ surveillance testing during and after treatment with BESPONSA. Based on the severity of myelosuppression, reduce dose, temporarily withhold, or permanently discontinue BESPONSA [see Dosage and Administration (2.3) ].

5.4 Infusion Related Reactions BESPONSA can cause infusion related reactions. […]

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 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. […]

7. DRUG INTERACTIONS 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) ] .

8. USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 )

8.1 Pregnancy Risk Summary Based on its mechanism of action and findings from animal studies [see Clinical Pharmacology (12.1) , Nonclinical Toxicology (13.1) ] , BESPONSA can cause embryo-fetal harm when administered to a pregnant woman . There are no available data on BESPONSA use in pregnant women to inform a drug-associated risk. In rat embryo-fetal development studies, inotuzumab ozogamicin caused embryo-fetal toxicity at maternal systemic exposures that were ≥ 0.4 times the exposure in patients at the maximum recommended dose, based on AUC [see Data ] . Advise patients of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies are 2–4% and 15–20%, respectively. Data Animal Data In embryo-fetal development studies in rats, pregnant animals received daily intravenous doses of inotuzumab ozogamicin up to 0.36 mg/m 2 during the period of organogenesis. Embryo-fetal toxicities including increased resorptions and fetal growth retardation as evidenced by decreased live fetal weights and delayed skeletal ossification were observed at ≥ 0.11 mg/m 2 (approximately 2 times the exposure in patients at the maximum recommended dose, based on AUC). Fetal growth retardation also occurred at 0.04 mg/m 2 (approximately 0.4 times the exposure in patients at the maximum recommended dose, based on AUC). In an embryo-fetal development study in rabbits, pregnant animals received daily intravenous doses up to 0.15 mg/m 2 (approximately 3 times the exposure in patients at the maximum recommended dose, based on AUC) during the period of organogenesis. At a dose of 0.15 mg/m 2 , slight maternal toxicity was observed in the absence of any effects on embryo‑fetal development.

8.2 Lactation Risk Summary There are no data on the presence of inotuzumab ozogamicin or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with BESPONSA and for 2 months after the last dose.

8.3 Females and Males of Reproductive Potential Based on its mechanism of action and findings from animal studies, BESPONSA can cause embryo-fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating BESPONSA. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with BESPONSA and for 8 months after the last dose [see Nonclinical Toxicology (13.1) ] . Males Advise males with female partners of reproductive potential to use effective contraception during treatment with BESPONSA and for 5 months after the last dose [see Nonclinical Toxicology (13.1) ] . Infertility Females Based on findings in animals, BESPONSA may impair fertility in females of reproductive potential [see Nonclinical Toxicology (13.1) ] . Males Based on findings in animals, BESPONSA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1) ] .

8.4 Pediatric Use The safety and effectiveness of BESPONSA in pediatric patients 1 year and older with relapsed or refractory CD22-positive B-cell precursor ALL have been established. The use of BESPONSA for this indication is supported by evidence of safety and effectiveness in Study WI203581 (ITCC-059) [see Adverse Reactions (6.1) , Clinical Studies (14.1) ] . The study included patients in the following age groups: 2 patients 1 year to < 2 years old, 10 patients 2 years to < 6 years old, 20 patients 6 years to < 12 years old, and 20 patients 12 years to < 17 years old. Compared to adults, pediatric patients had a higher incidence of liver test abnormalities; with grade 3-4 increases in AST, ALT, and total bilirubin in 21%, 21%, and 9%, respectively, in pediatric patients treated with BESPONSA compared to 4%, 4%, and 5% in adults. The safety and effectiveness of BESPONSA in patients < 1 year of age with relapsed or refractory CD22-positive B-cell precursor ALL have not been established.

8.5 Geriatric Use In the INO-VATE ALL trial, 30/164 patients (18%) treated with BESPONSA were ≥ 65 years of age. No differences in responses were identified between older and younger patients. Based on a population pharmacokinetic analysis in 765 patients, no adjustment to the starting dose is required based on age [see Clinical Pharmacology (12.3) ] .

8.6 Hepatic Impairment Based on a population pharmacokinetic analysis, the clearance of inotuzumab ozogamicin in patients with mild hepatic impairment (total bilirubin less than or equal to ULN and AST greater than ULN, or total bilirubin greater than 1.0–1.5 × ULN and AST any level; n=150) was similar to patients with normal hepatic function (total bilirubin/AST less than or equal to ULN; n=611). In patients with moderate (total bilirubin greater than 1.5–3 × ULN and AST any level; n=3) and severe hepatic impairment (total bilirubin greater than 3 × ULN and AST any level; n=1), inotuzumab ozogamicin clearance did not appear to be reduced [see Clinical Pharmacology (12.3) ]. No adjustment to the starting dose is required when administering BESPONSA to patients with total bilirubin less than or equal to 1.5 × ULN and AST/ALT less than or equal to 2.5 × ULN [see Dosage and Administration (2.3) ]. There is limited safety information available in patients with total bilirubin greater than 1.5 × ULN and/or AST/ALT greater than 2.5 × ULN prior to dosing. 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 Dosage and Administration (2.3) , Warnings and Precautions (5.1) ] .

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.