Besponsa Drug Information
Generic name: INOTUZUMAB OZOGAMICIN
CD22-directed Immunoconjugate [EPC]
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Uses of Besponsa
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.
Dosage & Administration of Besponsa
- 2. DOSAGE AND ADMINISTRATION
- Administer by intravenous infusion only.
- Pre-medicate with a corticosteroid, antipyretic, and antihistamine prior to all infusions.
- Dosing regimens for Cycle 1 and subsequent cycles, depending on the response to treatment, are shown below. Subsequent cycles are 4 weeks in duration. 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.
- 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 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 ≥ 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.: 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.
- 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 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. 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. Infusion related reaction Interrupt the infusion and institute appropriate medical management. For severe or life-threatening infusion reactions, permanently discontinue treatment. Table 4. BESPONSA Dosage Modifications Depending on Duration of Dosing Interruption Due to Non-Hematologic Toxicity Toxicities 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. 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.
| 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 | ||
| 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 | ||
| 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). |
| 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. |
| 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. |
| 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 |
| 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. |
Side Effects of Besponsa
- 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)
- Increased risk of post-transplant non-relapse mortality
- Myelosuppression
- Infusion related reactions
- QT interval prolongation 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. 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, mitoxantrone + cytarabine, or high dose cytarabine ) n= % 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. VOD was reported in 23/164 patients (14%) who received BESPONSA during or following treatment or following a HSCT after completion of treatment. 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. 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 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). Patients (n=53) received the recommended dosage of BESPONSA 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. 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 WI 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 0
| 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 |
| 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 |
| 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 |
| 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 |
Warnings & Cautions for Besponsa
- 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.
- Infusion related reactions: Monitor for infusion related reactions during and for at least 1 hour after infusion ends.
- 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.
- Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. 5.1 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). 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. 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. 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 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 of patients, respectively. 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. 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. The post-HSCT non-relapse mortality rate was 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. 5.3 Myelosuppression BESPONSA can cause myelosuppression, including thrombocytopenia and neutropenia. Febrile neutropenia, which may be life-threatening, occurred in 43/164 patients (26%). Complications associated with myelosuppression (including infections and bleeding/hemorrhage) occurred in patients receiving BESPONSA. 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%). The most common type of hemorrhage was epistaxis which occurred 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. Based on the severity of myelosuppression, reduce dose, temporarily withhold, or permanently discontinue BESPONSA. 5.4 Infusion Related Reactions BESPONSA can cause infusion related reactions. In adult patients in the INO-VATE ALL trial, infusion related reactions occurred in patients who received BESPONSA. Infusion related reactions (all Grade 2) occurred 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. In pediatric patients in Study WI203581 (ITCC-059), infusion related reactions occurred in 4/53 (8%) patients. Premedicate with a corticosteroid, antipyretic, and antihistamine prior to dosing. 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. 5.5 QT Interval Prolongation BESPONSA can cause QT interval prolongation. In adult patients 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 occurred in 4/162 patients (3%). Grade 2 QT prolongation was reported in 2/164 patients (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, and in patients with electrolyte disturbances. 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. 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 8 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with BESPONSA and for 5 months after the last dose. Advise 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.
Drug Interactions with Besponsa
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. 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.
Pregnancy Safety for Besponsa
Pregnancy Risk Summary Based on its mechanism of action and findings from animal studies, 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.
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.
Pediatric Use of Besponsa
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).
Contraindications for Besponsa
4. CONTRAINDICATIONS None. None
Clinical Studies of Besponsa
14. CLINICAL STUDIES Relapsed or Refractory ALL INO-VATE ALL Study – Adult Patients 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. 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.
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, of responding patients per EAC achieved CR/CRi in Cycles 1 and 2, respectively, in the BESPONSA arm, and of responding patients per EAC achieved a CR/CRi in Cycles 1 and 2, respectively, in the Investigator's choice of chemotherapy arm. Table 11 shows the efficacy results from this study.
Table 11. 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) WI203581 (ITCC-059) – Pediatric Patients BESPONSA was evaluated in a multicenter, single-arm, open-label study in 53 pediatric patients ≥ 1 and < 18 years of age with relapsed or refractory CD22-positive B-cell precursor ALL. Patients received a median of 2 cycles of therapy (range: 1 to 4 cycles).
Efficacy was established on the basis of the Complete Remission (CR) Rate, duration of CR, and proportion of patients with MRD negative CR. In all patients, patients achieved CR, and the median duration of CR (DOCR) was 8.2 months (95% CI: 2.6-NE). The minimal residual disease (MRD) negativity rate in patients with CR was 21/22 based on flow cytometry, and 19/22 based on RQ-PCR.
Figure 1
| CR CR, per EAC, was 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. | CRi CRi, per EAC, was 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. | CR/CRi, | ||||
|---|---|---|---|---|---|---|
| BESPONSA (N=109) | HIDAC, FLAG, or MXN/Ara-C (N=109) | BESPONSA (N=109) | HIDAC, FLAG or MXN/Ara-C (N=109) | BESPONSA (N=109) | HIDAC, FLAG, or MXN/Ara-C (N=109) | |
| Abbreviations: CI=confidence interval; CR=complete remission; CRi=complete remission with incomplete hematologic recovery; DoR=duration of remission; EAC=Endpoint Adjudication Committee; FLAG=fludarabine + cytarabine + granulocyte colony-stimulating factor; HIDAC=high-dose cytarabine; HR=hazard ratio; MRD=minimal residual disease; MXN/AraC=mitoxantrone + cytarabine; N/n=number of patients; OS=overall survival; PFS=progression-free survival. | ||||||
| Responding (CR/CRi) patients | ||||||
| n (%) [95% CI] | 39 (35.8) [26.8–45.5] | 19 (17.4) [10.8–25.9] | 49 (45.0) [35.4–54.8] | 13 (11.9) [6.5–19.5] | 88 (80.7) [72.1–87.7] | 32 (29.4) [21.0–38.8] |
| p-value 1-sided p-value using Chi-squared test. | < 0.0001 | |||||
| DoR DoR, based on a later cutoff date than the CR/CRi, was defined for patients who achieved CR/CRi per Investigator's assessment as time since first response of CR* or CRi per Investigator's assessment to the date of a PFS event or censoring date if no PFS event was documented. | ||||||
| n | 39 | 18 | 45 | 14 | 84 | 32 |
| Median, months [95% CI] | 8.0 [4.9–10.4] | 4.9 [2.9–7.2] | 4.6 [3.7–5.7] | 2.9 [0.6–5.7] | 5.4 [4.2–8.0] | 3.5 [2.9–6.6] |
| MRD-negativity MRD-negativity was defined by flow cytometry as leukemic cells comprising < 1 × 10 -4 (< 0.01%) of bone marrow nucleated cells. | ||||||
| n | 35 | 6 | 34 | 3 | 69 | 9 |
| Rate Rate was defined as the number of patients who achieved MRD negativity divided by the total number of patients who achieved CR/CRi per EAC. (%) [95% CI] | 35/39 (89.7) [75.8–97.1] | 6/19 (31.6) [12.6–56.6] | 34/49 (69.4) [54.6–81.7] | 3/13 (23.1) [5.0–53.8] | 69/88 (78.4) [68.4–86.5] | 9/32 (28.1) [13.7–46.7] |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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