Besponsa: Package Insert and Label Information (Page 4 of 4)

14. CLINICAL STUDIES

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.

Table 8. Efficacy Results in Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator’s Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC)

	CR *		CRi †		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.
* 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 × 109 /L and absolute neutrophil counts [ANC] ≥ 1 × 109 /L) and resolution of any extramedullary disease. † 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 × 109 /L and/or ANC < 1 × 109 /L) and resolution of any extramedullary disease. ‡ 1-sided p-value using Chi-squared test. § 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. ¶ MRD-negativity was defined by flow cytometry as leukemic cells comprising < 1 × 10-4 (< 0.01%) of bone marrow nucleated cells. # 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.
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 ‡					<0.0001
DoR §
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 ¶
n	35	6	34	3	69	9
Rate # (%)[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]

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)

15. REFERENCES

1. OSHA Hazardous Drugs. OSHA. [Accessed on 3 May 2017, from http://www.osha.gov/SLTC/hazardousdrugs/index.html]

16. HOW SUPPLIED/STORAGE AND HANDLING

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

17. PATIENT COUNSELING INFORMATION

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)].

This product’s label may have been updated. For current full prescribing information, please visit www.BESPONSA.com.

US License No. 003

LAB-0763-2.0

PRINCIPAL DISPLAY PANEL — 0.9 mg Vial Label

Pfizer

NDC 0008-0100-01
Rx only

BESPONSA ™
(inotuzumab ozogamicin)
for Injection

0.9 mg/vial

For Intravenous Infusion Only

No Preservatives

Single-dose vial. Discard unused portion.

PRINCIPAL DISPLAY PANEL — 0.9 mg Vial Carton

Pfizer

BESPONSA™
(inotuzumab ozogamicin)
for Injection

0.9 mg/vial

Each single-dose vial delivers 0.9 mg
inotuzumab ozogamicin, polysorbate 80
(0.36 mg), sodium chloride (2.16 mg),
sucrose (180 mg), and tromethamine(8.64 mg).

BESPONSA inotuzumab ozogamicin injection, powder, lyophilized, for solution

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0008-0100 Route of Administration INTRAVENOUS DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength INOTUZUMAB OZOGAMICIN (INOTUZUMAB OZOGAMICIN) INOTUZUMAB OZOGAMICIN 0.25 mg in 1 mL

Inactive Ingredients Ingredient Name Strength TROMETHAMINE SUCROSE POLYSORBATE 80 SODIUM CHLORIDE WATER

Packaging # Item Code Package Description Multilevel Packaging 1 NDC:0008-0100-01 1 VIAL, SINGLE-DOSE in 1 CARTON contains a VIAL, SINGLE-DOSE 1 4 mL in 1 VIAL, SINGLE-DOSE This package is contained within the CARTON (0008-0100-01)

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA761040 08/18/2017

Labeler — Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc. (113008515)

Establishment
Name	Address	ID/FEI	Operations
Pharmacia and Upjohn Company LLC		618054084	LABEL (0008-0100), PACK (0008-0100)

Establishment
Name	Address	ID/FEI	Operations
Wyeth BioPharma Division of Wyeth Pharmaceuticals LLC		174350868	ANALYSIS (0008-0100), API MANUFACTURE (0008-0100)

Establishment
Name	Address	ID/FEI	Operations
Wyeth Pharmaceutical Division of Wyeth Holdings LLC		054065909	ANALYSIS (0008-0100), API MANUFACTURE (0008-0100), MANUFACTURE (0008-0100)

Revised: 09/2020 Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc.