2.1 Recommended Dosage

• Pre-medicate before each dose [see Dosage and Administration (2.2)].
• For the first cycle, the recommended total dose of BESPONSA for all patients is 1.8 mg/m2 per cycle, administered as 3 divided doses on Day 1 (0.8 mg/m2), Day 8 (0.5 mg/m2), and Day 15 (0.5 mg/m2). 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/m2 per cycle, administered as 3 divided doses on Day 1 (0.5 mg/m2), Day 8 (0.5 mg/m2), and Day 15 (0.5 mg/m2). 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/m2 per cycle given as 3 divided doses on Day 1 (0.8 mg/m2), Day 8 (0.5 mg/m2), and Day 15 (0.5 mg/m2). 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.

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/mm3 is recommended prior to the first dose.

2.3 Dose Modification

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.

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.

5.1 Hepatotoxicity, Including Hepatic Veno-occlusive Disease (VOD) (also known as Sinusoidal Obstruction Syndrome)

In the INO-VATE ALL trial, hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic VOD was observed in 23/164 patients (14%) in the BESPONSA arm during or following treatment or following a HSCT after completion of treatment. VOD was reported up to 56 days after the last 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 was reported in 18/79 patients (23%), and among all 164 patients treated, VOD was reported 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.

Monitor closely for signs and symptoms of VOD; these may include 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 closely during the first month post-HSCT, then less frequently thereafter, according to standard medical practice.

In the INO-VATE ALL trial, increases in liver tests were reported. Grade 3/4 AST, ALT, and total bilirubin abnormal liver tests occurred in 7/160 (4%), 7/161 (4%), and 8/161 patients (5%), respectively.

In all patients, monitor liver tests, including ALT, AST, total bilirubin, and alkaline phosphatase, prior to and following each dose of BESPONSA. Elevations of liver tests may require dosing interruption, dose reduction, or permanent discontinuation of BESPONSA [see Dosage and Administration (2.3)].

5.2 Increased Risk of Post-Transplant Non-Relapse Mortality

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).

Monitor closely for toxicities post-HSCT, including signs and symptoms of infection and VOD [see Warnings and Precautions (5.1, 5.3)].

5.3 Myelosuppression

In the INO-VATE ALL trial, myelosuppression was observed in patients receiving BESPONSA [see Adverse Reactions (6.1)].

Thrombocytopenia and neutropenia were reported in 83/164 patients (51%) and 81/164 patients (49%), respectively. Grade 3 thrombocytopenia and neutropenia were reported in 23/164 patients (14%) and 33/164 patients (20%), respectively. Grade 4 thrombocytopenia and neutropenia were reported in 46/164 patients (28%) and 45/164 patients (27%), respectively. Febrile neutropenia, which may be life-threatening, was reported 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/mm3 was later than 45 days after the last 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/hemorrhagic events) were observed in patients receiving BESPONSA [see Adverse Reactions (6.1)]. Infections, including serious infections, some of which were life-threatening or fatal, were reported in 79/164 patients (48%). Fatal infections, including pneumonia, neutropenic sepsis, sepsis, septic shock, and pseudomonal sepsis, were reported in 8/164 patients (5%). Bacterial, viral, and fungal infections were reported.

Hemorrhagic events were reported in 54/164 patients (33%). Grade 3 or 4 hemorrhagic events were reported in 8/164 patients (5%). One Grade 5 (fatal) hemorrhagic event (intra-abdominal hemorrhage) was reported in 1/164 patients (1%). The most common hemorrhagic event was epistaxis which was reported in 24/164 patients (15%).

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. Management of severe infection, bleeding/hemorrhage, or other effects of myelosuppression, including severe neutropenia or thrombocytopenia, may require dosing interruption, dose reduction, or permanent discontinuation of BESPONSA [see Dosage and Administration (2.3)].

5.4 Infusion Related Reactions

In the INO-VATE ALL trial, infusion related reactions were observed in patients who received BESPONSA. Infusion related reactions (all Grade 2) were reported in 4/164 patients (2%). Infusion related reactions generally occurred in Cycle 1 shortly after the end of the BESPONSA infusion and resolved spontaneously or with medical management.

Premedicate with a corticosteroid, antipyretic, and antihistamine prior to dosing [see Dosage and Administration (2.2)].

Monitor patients closely during and for at least 1 hour after the end of infusion for the potential onset of infusion related reactions, including symptoms such as fever, chills, rash, or breathing problems. Interrupt infusion and institute appropriate medical management if an infusion related reaction occurs. 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 BESPONSA [see Dosage and Administration (2.3)].

5.5 QT Interval Prolongation

In the INO-VATE ALL trial, increases in QT interval corrected for heart rate using Fridericia's formula (QTcF) of ≥ to 60 msec from baseline were measured in 4/162 patients (3%). No patients had QTcF values greater than 500 msec [see Clinical Pharmacology (12.2)]. Grade 2 QT prolongation was reported in 2/164 patients (1%). No ≥ Grade 3 QT prolongation or events of Torsade de Pointes were reported [see Adverse Reactions (6.1)].

Administer BESPONSA with caution in patients who have a history of or predisposition for QTc prolongation, who are taking medicinal products that are known to prolong QT interval [see Drug Interactions (7)], and in patients with electrolyte disturbances [see Drug Interactions (7)]. Obtain electrocardiograms (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 Drug Interactions (7), Clinical Pharmacology (12.2)]).

5.6 Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, BESPONSA can cause embryo-fetal harm when administered to a pregnant woman. In animal studies, inotuzumab ozogamicin caused embryo-fetal toxicities, starting at a dose that was approximately 0.4 times the exposure in patients at the maximum recommended dose, based on the area under the concentration-time curve (AUC). Advise females of reproductive potential to use effective contraception during treatment with BESPONSA and for at least 8 months after the final dose of BESPONSA. Advise males with female partners of reproductive potential to use effective contraception during treatment with BESPONSA and for at least 5 months after the last dose of BESPONSA. Apprise pregnant women of the potential risk to the fetus. Advise women to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with BESPONSA [see Use in Specific Populations (8.1, 8.3), Clinical Pharmacology (12.1), Nonclinical Toxicology (13.1)].

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.

The adverse reactions described in this section reflect exposure to BESPONSA in 164 patients with relapsed or refractory ALL who participated in a randomized clinical study of BESPONSA versus Investigator's choice of chemotherapy (fludarabine + cytarabine + granulocyte colony-stimulating factor [FLAG], mitoxantrone + cytarabine [MXN/Ara-C], or high dose cytarabine [HIDAC]) (INO-VATE ALL Trial [NCT01564784]) [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 6 shows the adverse reactions with ≥ 10% incidence reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy.

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 7 shows the clinically important laboratory abnormalities reported in patients with relapsed or refractory ALL who received BESPONSA or Investigator's choice of chemotherapy.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to inotuzumab ozogamicin in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In clinical studies of BESPONSA in patients with relapsed or refractory ALL, the immunogenicity of BESPONSA was evaluated using an electrochemiluminescence (ECL)-based immunoassay to test for anti-inotuzumab ozogamicin antibodies. For patients whose sera tested positive for anti-inotuzumab ozogamicin antibodies, a cell-based luminescence assay was performed to detect neutralizing antibodies.

In clinical studies of BESPONSA in patients with relapsed or refractory ALL, 7/236 patients (3%) tested positive for anti-inotuzumab ozogamicin antibodies. No patients tested positive for neutralizing anti-inotuzumab ozogamicin antibodies. In patients who tested positive for anti-inotuzumab ozogamicin antibodies, the presence of anti-inotuzumab ozogamicin antibodies did not affect clearance following BESPONSA treatment.

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)].

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

Safety and effectiveness have not been established in pediatric patients.

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)].

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.

12.2 Pharmacodynamics

During the treatment period, the pharmacodynamic response to BESPONSA was characterized by the depletion of CD22-positive leukemic blasts.

12.3 Pharmacokinetics

The mean Cmax of inotuzumab ozogamicin was 308 ng/mL. The mean simulated total AUC per cycle was 100,000 ng∙h/mL. In patients with relapsed or refractory ALL, steady-state drug concentration was achieved by Cycle 4. Following administration of multiple doses, a 5.3 times accumulation of inotuzumab ozogamicin was predicted by Cycle 4.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Formal carcinogenicity studies have not been conducted with inotuzumab ozogamicin. In toxicity studies, rats were dosed weekly for 4 or 26 weeks with inotuzumab ozogamicin at doses up to 4.1 mg/m2 and 0.73 mg/m2, respectively. After 26 weeks of dosing, rats developed hepatocellular adenomas in the liver at 0.73 mg/m2 (approximately 2 times the exposure in patients at the maximum recommended dose, based on AUC).

Inotuzumab ozogamicin was clastogenic in vivo in the bone marrow of male mice that received single doses ≥1.1 mg/m2. This is consistent with the known induction of DNA breaks by calicheamicin. N-acetyl-gamma-calicheamicin dimethylhydrazide (the cytotoxic agent released from inotuzumab ozogamicin) was mutagenic in an in vitro bacterial reverse mutation (Ames) assay.

In a female fertility and early embryonic development study, female rats were administered daily intravenous doses of inotuzumab ozogamicin up to 0.11 mg/m2 for 2 weeks before mating through Day 7 of pregnancy. An increase in the proportion of resorptions and decrease in the number of viable embryos and gravid uterine weights were observed at the 0.11 mg/m2 dose level (approximately 2 times the exposure in patients at the maximum recommended dose, based on AUC). Additional findings in female reproductive organs occurred in repeat-dose toxicology studies and included decreased ovarian and uterine weights, and ovarian and uterine atrophy. Findings in male reproductive organs occurred in repeat-dose toxicology studies and included decreased testicular weights, testicular degeneration, hypospermia, and prostatic and seminal vesicle atrophy. Testicular degeneration and hypospermia were nonreversible following a 4-week nondosing period. In the chronic studies of 26-weeks duration, adverse effects on reproductive organs occurred at ≥0.07 mg/m2 in male rats and at 0.73 mg/m2 in female monkeys [see Use in Specific Populations (8.3)].

Patients With Relapsed or Refractory ALL – INO-VATE ALL

The safety and efficacy of BESPONSA were evaluated in INO-VATE ALL (NCT01564784) a randomized (1:1), open-label, international, multicenter study in patients with relapsed or refractory ALL. Patients were stratified at randomization based on duration of first remission (< 12 months or ≥ 12 months, salvage treatment (Salvage 1 or 2) and patient age at randomization (< 55 or ≥ 55 years). Eligible patients were ≥ 18 years of age with Philadelphia chromosome-negative or Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL. All patients were required to have ≥ 5% bone marrow blasts and to have received 1 or 2 previous induction chemotherapy regimens for ALL. Patients with Philadelphia chromosome-positive B-cell precursor ALL were required to have disease that failed treatment with at least 1 tyrosine kinase inhibitor and standard chemotherapy. Table 1 shows the dosing regimen used to treat patients.

Among all 326 patients who were randomized to receive BESPONSA (N=164) or Investigator's choice of chemotherapy (N=162), 215 patients (66%) had received 1 prior treatment regimen for ALL and 108 patients (33%) had received 2 prior treatment regimens for ALL. The median age was 47 years (range: 18–79 years), 276 patients (85%) had Philadelphia chromosome-negative ALL, 206 patients (63%) had a duration of first remission < 12 months, and 55 patients (17%) had undergone a HSCT prior to receiving BESPONSA or Investigator's choice of chemotherapy. The two treatment groups were generally balanced with respect to the baseline demographics and disease characteristics.

All evaluable patients had B-cell precursor ALL that expressed CD22, with ≥ 90% of evaluable patients exhibiting ≥ 70% leukemic blast CD22 positivity prior to treatment, as assessed by flow cytometry performed at a central laboratory.

The efficacy of BESPONSA was established on the basis of CR, the duration of CR, and proportion of MRD-negative CR (< 1 × 10-4 of bone marrow nucleated cells by flow cytometry) in the first 218 patients randomized. CR, duration of remission (DoR), and MRD results in the initial 218 randomized patients were consistent with those seen in all 326 randomized patients.

Among the initial 218 randomized patients, 64/88 (73%) and 21/88 (24%) of responding patients per EAC achieved CR/CRi in Cycles 1 and 2, respectively, in the BESPONSA arm, and 29/32 (91%) and 1/32 (3%) of responding patients per EAC achieved a CR/CRi in Cycles 1 and 2, respectively, in the Investigator's choice of chemotherapy arm.

Table 8 shows the efficacy results from this study.

Among the initial 218 patients, as per EAC assessment, 32/109 patients (29%) in the BESPONSA arm achieved complete remission with partial hematologic recovery (CRh; defined as <5% blasts in the bone marrow, ANC > 0.5 × 109/L, and platelet counts > 50 × 109/L but not meeting full recovery of peripheral blood counts) versus 6/109 patients (6%) in the Investigator's choice of chemotherapy arm, and 71/109 patients (65%) in the BESPONSA arm achieved CR/CRh versus 25/109 patients (23%) in the Investigator's choice of chemotherapy arm.

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.

Figure 1 shows the analysis of overall survival (OS). The analysis of OS did not meet the pre-specified boundary for statistical significance.

Figure 1. Kaplan-Meier Curve for Overall Survival (Intent-to-Treat Population)

16.1 How Supplied

BESPONSA (inotuzumab ozogamicin) for Injection is supplied as a white to off-white lyophilized powder in a single-dose vial for reconstitution and further dilution. Each vial delivers 0.9 mg inotuzumab ozogamicin. Each carton (NDC 0008-0100-01) contains one single-dose vial.

16.2 Storage and Handling

Refrigerate (2–8°C; 36–46°F) BESPONSA vials and store in the original carton to protect from light. Do not freeze.

BESPONSA is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

Hepatotoxicity, Including Hepatic Veno-occlusive Disease (VOD) (also known as Sinusoidal Obstruction Syndrome)

Inform patients that liver problems, including severe, life-threatening, or fatal VOD, and increases in liver tests may develop during BESPONSA treatment. Inform patients that they should seek immediate medical advice if they experience symptoms of VOD, which may include elevated bilirubin, rapid weight gain, and abdominal swelling that may be painful. Inform patients that they should carefully consider the benefit/risk of BESPONSA treatment if they have a prior history of VOD or serious ongoing liver disease [see Warnings and Precautions (5.1)].

Increased Risk of Post-HSCT Non-Relapse Mortality

Inform patients that there is an increased risk of post-HSCT non-relapse mortality after receiving BESPONSA, that the most common causes of post-HSCT non-relapse mortality included infection and VOD. Advise patients to report signs and symptoms of infection [see Warnings and Precautions (5.2)].

Myelosuppression

Inform patients that decreased blood counts, which may be life-threatening, may develop during BESPONSA treatment and that complications associated with decreased blood counts may include infections, which may be life-threatening or fatal, and bleeding/hemorrhage events. Inform patients that signs and symptoms of infection, bleeding/hemorrhage, or other effects of decreased blood counts should be reported during treatment with BESPONSA [see Warnings and Precautions (5.3)].

Infusion Related Reactions

Advise patients to contact their health care provider if they experience symptoms such as fever, chills, rash, or breathing problems during the infusion of BESPONSA [see Warnings and Precautions (5.4)].

QT Interval Prolongation

Inform patients of symptoms that may be indicative of significant QTc prolongation including dizziness, lightheadedness, and syncope. Advise patients to report these symptoms and the use of all medications to their healthcare provider [see Warnings and Precautions (5.5)].

Embryo-Fetal Toxicity

Advise males and females of reproductive potential to use effective contraception during BESPONSA treatment and for at least 5 and 8 months after the last dose, respectively [see Use in Specific Populations (8.3)]. Advise females of reproductive potential to avoid becoming pregnant while receiving BESPONSA. Advise women to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with BESPONSA. Inform the patient of the potential risk to the fetus [see Warnings and Precautions (5.7), Use in Specific Populations (8.1)].

Lactation

Advise women against breastfeeding while receiving BESPONSA and for 2 months after the last dose [see Use in Specific Populations (8.2)].