Drugs

Drug Trials Snapshots: BESPONSA

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The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race, and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

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BESPONSA (inotuzumab ozogamicin)
bee SPON’sah
Pfizer Inc.
Approval date: August 17, 2017


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

BESPONSA is used to treat adults with B-cell acute lymphoblastic leukemia (ALL) whose disease has come back or has not improved after previous treatment(s).

ALL is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of lymphocytes, a type of white blood cells, in the bloodstream.

How is this drug used?

BESPONSA is given by a healthcare provider directly into the bloodstream through a needle in the vein. This is known as an intravenous, or IV infusion. It takes about one hour to receive BESPONSA infusion.

BESPONSA is given once a week for the first three weeks of the treatment Cycle 1 and then according to a special schedule depending on the response.

What are the benefits of this drug?

36 percent of the 109 patients who received BESPONSA experienced no evidence of disease and full recovery of blood counts after treatment (complete remission) which lasted about 8 months. In comparison, 17 percent of the 109 patients who received other medications to treat ALL experience a complete remission that lasted about 5 months.

What are the benefits of this drug (results of trials used to assess efficacy)?

The table below summarizes efficacy results established on the basis of the complete response (CR), duration of remission (DoR), and minimal residual disease (MRD) results in the initial 218 randomized patients. Results in these patients were consistent with those seen in all 326 randomized patients.

Table 2: 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)

 CRaCRibCR/CRia,b
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)
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-valuec  <0.0001
DoRd
n391845148432
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-negativitye
n356343699
Ratef (%) [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]

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.

a 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.
b 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.
c 1-sided p-value using Chi-squared test.
d 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 CRa or CRib per Investigator’s assessment to the date of a PFS event or censoring date if no PFS event was documented.
e MRD-negativity was defined by flow cytometry as leukemic cells comprising < 1 × 10-4 (< 0.01%) of bone marrow nucleated cells.
f 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.

BESPONSA Prescribing Information

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

  • Sex: BESPONSA worked similarly in men and women.
  • Race: Most of the patients were White. Differences in how well the drug worked among races could not be determined because of the small number of patients in other races.
  • Age: BESPONSA worked similarly in patients younger and older than 55 years of age.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

The table below summarizes efficacy results by demographic subgroups. Because of the small sample sizes, these exploratory analyses should be interpreted with caution.

Table 3. Subgroup Analyses of Complete Response Rate by Sex, Race, Age, and Region

 BESPONSA N=109Investigator’s Choice N=109Rate Difference (97.5% CI)
Sex
Men, n
Rate
Women, n
Rate
61
45 (75.4)
48
39 (81.3)
73
17 (23.3)
36
14(38.9)
52.1
(35.5, 68.7)
42.4
(20.2, 64.5)
Race
White, n
Rate
Black, n
Rate
Asian, n
Rate
Other, n
Rate
76
62 (81.6)
1
0
17
14 (82.4)
15
9 (60.0)
79
23 (29.1)
2
1 (50.0)
17
3 (17.6)
11
4 (36.4)
52.5
(37.3, 67.6)
-50.0
(-100.0, 29.2)
64.7
(35.4, 94.0)
23.6
(-19.5, 66.8)
Age
<55 year, n
Rate
(95% CI)
≥55 year, n
Rate
(95% CI)
66
53 (80.3)
(68.7, 89.1)
43
35 (81.4)
(66.6, 91.6)
69
22 (31.9)
(21.2, 44.2)
40
10 (25.0)
(12.7, 41.2)
48.4
(31.7, 65.1)

56.4
(36.1, 76.7)
 
Region
Asia, n
Rate
North America, n
Rate
EU, n
Rate
Others, n
Rate
14
12 (85.7)
48
35 (72.9)
45
37 (82.2)
2
1 (50.0)
7
2 (28.6)
52
13 (25.0)
47
15 (31.9)
3
1 (33.3)
57.1
(13.5, 100.0)
47.9
(28.2, 67.6)
50.3
(30.4, 70.2)
16.7
(-83.3, 100.0)

Adapted from FDA review

What are the possible side effects?

BESPONSA may cause serious and life threating liver damage. Other serious side effects include increased death rate after stem-cell transplant, bone marrow suppression, heart rhythm problems due to QT prolongation and infusion reactions.

The most common side effects of BESPONSA are low blood cell counts, infection, tiredness, bleeding, fever, nausea, headache and increase in liver tests.

What are the possible side effects (results of trials used to assess safety)?

The tables below summarize adverse reactions and laboratory abnormalities in the clinical trial. Adverse reactions included treatment-emergent all-causality events that commenced on or after Cycle 1 Day 1 within 42 days after the last dose of BESPONSA, but prior to the start of a new anticancer treatment (including HSCT).

Table 4. Adverse Reactions With ≥ 10% Incidencea 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)

Body System Adverse ReactionBESPONSA
(N=164)
FLAG, MXN/Ara-C, or
HIDAC
(N=143b)
All Grades≥ Grade 3All Grades≥ Grade 3
%%%%
Infections
Infectionc48287654
Blood and lymphatic system disorders
Thrombocytopeniad51426159
Neutropeniae49484543
Anemiaf36245947
Leukopeniag35334342
Febrile neutropenia26265353
Lymphopeniah18162726
Metabolism and nutrition disorders
Decreased appetite121132
Nervous system disorders
HeadacheI282271
Vascular disorders
Hemorrhagej335285
Gastrointestinal disorders
Nausea312460
Abdominal paink233231
Diarrhea171381
Constipation160240
Vomiting151240
Stomatitisl132263
Hepatobiliary disorders
Hyperbilirubinemia215176
General disorders and administration site conditions
Fatiguem355253
Pyrexia323426
Chills110110
Investigations
Transaminases increasedn267135
Gamma-glutamyltransferase increased211084
Alkaline phosphatase increased13270

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.

a Only adverse reactions with ≥ 10% incidence in the BESPONSA arm are included.
b 19 patients randomized to FLAG, MXN/Ara-C, or HIDAC did not receive treatment.
c Infection includes any reported preferred terms for BESPONSA retrieved in the System Organ Class Infections and infestations.
d Thrombocytopenia includes the following reported preferred terms: Platelet count decreased and Thrombocytopenia.
e Neutropenia includes the following reported preferred terms: Neutropenia and Neutrophil count decreased.
f Anemia includes the following reported preferred terms: Anemia and Hemoglobin decreased.
g Leukopenia includes the following reported preferred terms: Leukopenia, Monocytopenia, and White blood cell count decreased.
h Lymphopenia includes the following reported preferred terms: B-lymphocyte count decreased, Lymphocyte count decreased, and Lymphopenia.
I Headache includes the following reported preferred terms: Headache, Migraine, and Sinus headache.
j 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.
k Abdominal pain includes the following reported preferred terms: Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal tenderness, Esophageal pain, and Hepatic pain.
l Stomatitis includes the following reported preferred terms: Aphthous ulcer, Mucosal inflammation, Mouth ulceration, Oral pain, Oropharyngeal pain, and Stomatitis.
m Fatigue includes the following reported preferred terms: Asthenia and Fatigue.
n Transaminases increased includes the following reported preferred terms: Aspartate aminotransferase increased, Alanine aminotransferase increased, Hepatocellular injury, and Hypertransaminasemia.

BESPONSA Prescribing Information

Table 5. Laboratory Abnormalities in Patients with Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA or Investigator’s Choice of Chemotherapy (FLAG, MXN/Ara-C, or HIDAC)

Laboratory AbnormalityaNBESPONSANFLAG, MXN/Ara-C, or HIDAC
All GradesGrade 3/4All GradesGrade 3/4
%%%%
Hematology
Platelet count decreased161987614210099
Hemoglobin decreased161944014210070
Leukocytes decreased16195821429998
Neutrophil count decreased16094861309388
Lymphocytes (absolute) decreased16093711279791
Chemistry
GGT increased14867181116817
AST increased160714134384
ALP increased158571133523
ALT increased161494137464
Blood bilirubin increased161365138356
Lipase increased139321390202
Hyperuricemia158163122110
Amylase increased14315210291

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.

a Laboratory abnormalities were summarized up to the end of treatment + 42 days but prior to the start of a new anti-cancer therapy.

BESPONSA Prescribing Information

 

Were there any differences in side effects among sex, race and age?

  • Sex: The occurrence of side effects was similar in men and women.
  • Race: Most of the patients were White. Differences in the occurrence of side effects among races could not be determined because of the small number of patients in other races.
  • Age: The occurrence of side effects was similar in patients younger and older than 55 years of age.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

Table below summarizes hepatotoxicity events during the clinical trials by sex, age and race subgroup. Because of the small sample sizes, these exploratory analyses should be interpreted with caution.

Table 6. Subgroup Analyses of Hepatotoxicity Adverse Events

  Demographic SubgroupBESPONSA
N=164
Investigator Choice
N=143
Relative Risk
(95% CI)
n (%)Total, Nn (%)Total, N
Overall43 (26.2)16425 (17.5)1431.50 (0.97, 2.33)
SEX
Men31 (34.1)9117 (18.5)921.84 (1.10, 3.09)
Women12 (16.4)738 (15.7)511.05 (0.46, 2.38)
AGE
< 55 years26 (25.0)10417 (18.7)911.34 (0.78, 2.30)
>= 55 years17 (28.3)608 (15.4)521.84 (0.87, 3.91)
RACE
White31 (27.7)11219 (18.1)1051.53 (0.92, 2.54)
Black or African American2 (50.0)41 (33.3)31.50 (0.23, 9.80)
Asian6 (19.4)312 (10.0)201.94 (0.43, 8.66)
American Indian0 (0.0)00 (0.0)0--
Native Hawaiian0 (0.0)00 (0.0)0--
Other4 (23.5)173 (20.0)151.18 (0.31, 4.43)
Missing Race0 (0.0)00 (0.0)0--
REGION
Asia5 (19.2)262 (13.3)151.44 (0.32, 6.54)
EU20 (32.8)619 (16.7)541.97 (0.98, 3.95)
North America17 (22.7)7514 (18.9)741.20 (0.64, 2.25)
Others1 (50.0)20 (0.0)0--

FDA Review

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved BESPONSA based on evidence from one clinical trial (INO-VATE ALL [NCT01564784]) that enrolled 326 patients with ALL whose disease has come back or has not improved after previous treatment(s).

The trial was conducted in United States, Canada, European Union, Japan, Korea, Singapore, Taiwan and Australia.

Figure 1 summarizes how many men and women were in the clinical trial.

Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many men and women were in the clinical trial. In total, 193 men (59%) and 133 women (41%) participated in the clinical trial.

FDA review

Figure 2. Baseline Demographics by Race

Pie chart summarizing the percentage of patients by race enrolled in the clinical trial. In total, 232 Whites (71%), 7 Black or African Americans (2%), 55 Asians (17%)  and 32 all Other (10%) participated in the clinical trial.

FDA review

Table 1. Baseline Demographics by Race

RaceNumber of PatientsPercentage
White23271
Black or African American72
Asian5517
Other3210

FDA review

Figure 3 summarizes how many patients of certain age were enrolled in the clinical trial.

Figure 3. Baseline Demographics by Age

Pie chart summarizing how many individuals of certain age groups were in the clinical trial.  In total, 207 patients were less than 55 years old (63%) and 119 were 55 and older (37%).)

FDA review

Who participated in the trials?

The table below summarizes demographics of all patients enrolled in the clinical trial.

Table 7. Baseline Demographics of Patients Enrolled in the Clinical Trial

Demographic
Characteristic
BESPONSA
N=164
Active Comparator
(Investigator’s Choice)
N=162
Total
N=326
Sex
Men
Women

91 (55.5)
73 (44.5)

102 (63.0)
60 (37.0)

193 (59)
133 (41)
Race
White
Black or African American
Asian
Other

112 (68.3)
4 (2.4)
31 (18.9)
17 (10.4)

120 (74.1)
3 (1.9)
24 (14.8)
15 (9.3)

232 (71)
7 (2)
55 (17)
32 (10)
Age
<55 years
≥55 years

104 (63.4)
60 (36.6)

103 (63.6)
59 (36.4)

207 (63)
119 (37)

FDA review

Table 8 . Baseline Demographics of Patients (ITT population)

Demographic CharacteristicBESPONSA
N=109
Active Comparator
(Investigator’s Choice) N=109
Sex, n (%)
Men
Women

61
48

73
36
Race, n (%)
White
Black or African American
Asian
Other

76 (69.7)
1 (0.9)
17 (15.6)
15 (13.8)

79 (72.5)
2 (1.8)
17 (15.6)
11 (10.1)
Age, n (%)
<55 years
≥55 years
≥65 years

66 (60.6)
43 (39.4)
23 (21.1)

69 (63.3)
40 (36.7)
14 (12.8)

FDA review

How were the trials designed?

There was one trial that evaluated the benefit and side effects of BESPONSA in patients with ALL whose disease has come back or has not improved after previous treatment(s). All patients had a certain type of ALL called B cell precursor ALL.

Patients received either BESPONSA infusion once a day or some other type of treatment for ALL per investigator’s choice. Both, patients and investigators knew which treatment has been given.

The benefit of BESPONSA was evaluated in the first 218 patients by measuring

  • how many patients reached complete remission (no evidence of disease) with full or partial recovery of blood counts after treatment,
  • how long those patients remained in remission, and
  • how many patients did not show signs of minimal disease in the bone marrow.

How were the trials designed?

The safety and efficacy of BESPONSA were established in one active-controlled, randomized (1:1), open label, multicenter trial in patients with relapsed or refractory ALL. Patients were ≥ 18 years of age with Philadelphia chromosome-negative or Philadelphia chromosome-positive relapsed or refractory B cell precursor ALL.

Patients received BESPONSA or Investigator’s choice of chemotherapy (fludarabine + cytarabine + granulocyte colony-stimulating factor [FLAG], mitoxantrone + cytarabine [MXN/Ara-C], or high dose cytarabine [HIDAC]) until disease progression or unacceptable toxicity.

The efficacy was established on the basis of the rate of CR, the duration of CR, and proportion of MRD-negative CR (< 1 x 10-4 of bone marrow nucleated cells by flow cytometry) in the first 218 patients randomized.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PRESCRIBING INFORMATION

Back to Drug Trials Snapshots

Page Last Updated: 08/30/2017
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