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Drug Trial Snapshot: XOSPATA

HOW TO USE THIS SNAPSHOT
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.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to XOSPATA Prescribing Information for complete information.

XOSPATA (gilteritinib)
zoh spah' tah
Astellas Pharma
Approval date:November 28, 2018


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

XOSPATA is used to treat adults with acute myeloid leukemia (AML) that have a mutation in a gene called FLT3 and whose disease has come back or has not improved after previous treatment(s).

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

How is this drug used?

XOSPATA is a tablet. Three tablets (total of 120 mg) are taken once a day.

What are the benefits of this drug?

Twenty-nine patients (21%) of the 138 patients who received XOSPATA experienced no evidence of disease and full or partial recovery of blood counts after treatment. Of the 106 patients who required red blood cell or platelet transfusions at the start of treatment with XOSPATA, 31 percent became transfusion-free for at least 56 days.

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 rate of complete remission (CR)/complete remission with partial hematologic recovery (CRh), the duration of CR/CRh (DOR), and the rate of conversion from transfusion dependence.

Table 2: Efficacy Results in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML)-Trial 1

Remission Rate

XOSPATA
N=138

CR*/CRh n/N (%)

29/138 (21)

95% CI‡

14.5, 28.8

Median DOR§ (months)

4.6

Range (months)

0.1 to 15.8¶

CR* n/N (%)

16/138 (11.6)

95% CI‡

6.8, 18.1

Median DOR§ (months)

8.6

Range (months)

1 to 13.8

CRh n/N (%)

13/138 (9.4)

95% CI‡

5.1, 15.6

Median DOR§ (months)

2.9

Range (months)

0.1 to 15.8¶

CI: confidence interval; NE: not estimable; NR: not reached; Only responses prior to HSCT were included in response rate.

*CR was defined as an absolute neutrophil count ≥1.0 x 109/L, platelets ≥100 x 109/L, normal marrow differential with <5% blasts, must have been red blood cells, platelet transfusion independent and no evidence of extramedullary leukemia.

†CRh was defined as marrow blasts <5%, partial hematologic recovery absolute neutrophil count ≥0.5 x 109/L and platelets ≥50 x 109/L, no evidence of extramedullary leukemia and could not have been classified as CR.

‡The 95% CI rate was calculated using the exact method based on binomial distribution.

§DOR was defined as the time from the date of either first CR or CRh until the date of a documented relapse of any type.

Deaths were counted as events.

¶Response was ongoing.

XOSPATA Prescribing Information

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

  • Sex: XOSPATA worked similarly in men and women.
  • Race: XOSPATA worked similarly in White and Asian patients. Differences in how well the drug worked among other races could not be determined because of the small number of patients of other races.
  • Age: XOSPATA worked similarly in patients younger and older than 65 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. These analyses were exploratory and therefore should be interpreted with caution.

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

Subgroup

CR/CRh (%)

95% CI

Sex

Men (n=64)

10 (15.6)

(7.8, 26.9)

Women (n=74)

19 (25.7)

(16.2, 37.2)

Race

White (n=82)

22 (26.8)

(17.6, 37.8)

Black or African American (n=10)

0 (0)

(NA, NA)

Asian (n=37)

7 (18.9)

(8.0, 35.2)

Other (n=9)

0 (0)

(NA, NA)

Age (years)

<65 (n=85)

15 (17.7)

(10.2, 27.4)

≥65 (n=53)

14 (26.4)

(15.3, 40.3)

Adapted from FDA Review

What are the possible side effects?

XOSPATA may cause serious side effects including condition called posterior reversible encephalopathy syndrome (PRES). PRES is characterized by seizures, quickly worsening headache, and mental status and vision changes. Other serious side effects include heart rhythm problems (because of QT prolongation), inflammation of pancreas and a harm to unborn baby.

The most common side effects of XOSPATA are muscle and joint pain, fatigue and elevated liver enzymes.

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

The tables below summarize adverse reactions and laboratory abnormalities that occurred in patients from the combined three clinical trials.

Table 4. Adverse Reactions Reported in ≥10% (Any Grade) or ≥5% (Grade 3-5) of Patients with Relapsed or Refractory AML

Body System
Adverse Reaction

XOSPATA
N=292

Any Grade
n (%)

Grade ≥3*
n (%)

Musculoskeletal and Connective Tissue Disorders

Myalgia/arthralgia†             

123 (42)

13 (5)

Investigations

Transaminase increased‡

121 (41)

47 (16)

Bilirubin increase                               §

31 (11)

14 (5)

General Disorders and Administration Site Conditions

Fatigue/malaise¶

116 (40)

14 (5)

Fever#

103 (35)

13 (5)

Edemaþ

100 (34)

5 (2)

Noninfectious diarrheaß

99 (34)

8 (3)

Constipation

80 (27)

2 (<1)

Nausea

78 (27)

4 (1)

Stomatitisà

77 (26)

11 (4)

Vomitingè

58 (20)

3 (1)

Respiratory, Thoracic and Mediastinal Disorders

Dyspneað

98 (34)

36 (12)

Cough

74 (25)

1 (<1)

Skin and subcutaneous tissue disorders

Rashø

87 (30)

8 (3)

Infections and Infestations

Pneumoniaý

89 (30)

66 (23)

Sepsis₤

43 (15)

41 (14)

Vascular disorders

Hypotension¥

60 (21)

21 (7)

HypertensionŒ

30 (10)

17 (6)

Nervous System Disorders

Headacheɶ

60 (21)

4 (1)

DizzinessÐ

57 (20)

1 (<1)

Dysgeusia

31 (11)

0

Renal and urinary disorders

Renal impairmentA

54 (19)

11 (4)

Gastrointestinal Disorders

Abdominal painB

50 (17)

5 (2)

Metabolism and Nutrition disorders

Decreased appetite

44 (15)

6 (2)

Psychiatric Disorders

Insomnia

42 (14)

1 (<1)

*Grade 3-5 includes serious, life-threatening and fatal adverse reactions
†Grouped terms: arthralgia, back pain, bone pain, myalgia, musculoskeletal pain, neck pain, non-cardiac chest pain, pain and pain in extremity
‡Grouped terms: aspartate aminotransferase increased, alanine aminotransferase increased, transaminases increased, liver function test increased, hepatic failure, hepatocellular injury and hepatotoxicity
§Grouped terms: blood bilirubin increased and hyperbilirubinemia
¶Grouped terms: asthenia, fatigue and malaise
#Grouped terms: body temperature increased and fever
þGrouped terms: edema, face edema, fluid retention, generalized edema, localized edema, edema peripheral, peripheral swelling and swelling face
ßGrouped terms: diarrhea and diarrhea hemorrhagic
àGrouped terms: aphthous ulcer, mucosal inflammation, mouth hemorrhage, mouth ulceration, oral mucosal blistering, oral mucosal erythema, stomatitis and tongue ulceration
èGrouped terms: hematemesis and vomiting
ðGrouped terms: acute respiratory failure, acute respiratory distress syndrome, dyspnea, dyspnea exertional, hypoxia, pulmonary edema, respiratory distress, respiratory failure, tachypnea and wheezing
øGrouped terms: dermatitis, dermatitis bullous, dermatitis contact, drug eruption, dermatitis exfoliative, eczema asteatotic, lichen planus, erythema, palmar-plantar erythrodysethesia syndrome, photosensitivity reaction, psoriasis, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculo-papular, rash papular, rash pruritic, seborrheic dermatitis, skin exfoliation and toxic skin eruption
ýGrouped terms: pneumonia, lung infection, pneumonia fungal, respiratory syncytial virus infection, respiratory tract infection, lung infiltration, organizing pneumonia, lower respiratory tract infection bacterial, pneumonia aspiration, pneumonitis, interstitial lung disease, lower respiratory tract infection and pneumonia viral
₤Grouped terms: sepsis, bacteremia, septic shock, bacterial sepsis and neutropenic sepsis
¥Grouped terms: blood pressure decreased, hypotension and orthostatic hypotension
ŒGrouped terms: blood pressure increased, hypertension and orthostatic hypertension
ɶGrouped terms: headache and tension headache
ÐGrouped terms: dizziness, dizziness postural and vertigo
AGrouped terms: acute kidney injury, blood creatinine increased, chronic kidney disease, oliguria, renal disorder, renal failure, renal impairment, renal injury and renal tubular necrosis
BGrouped terms: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, epigastric discomfort and gastrointestinal pain

XOSPATA Prescribing Information

Table 5. Most Common (≥20%) New or Worsening Laboratory Abnormalities Reported in Patients with Relapsed or Refractory AML

Parameter

XOSPATA
N=292

Any Grade
n (%)

Grade ≥3*
n (%)

 

Creatinine increased

273 (94)

10 (3)

 

Hyperglycemia

252 (86)

26 (9)

 

Hypertriglyceridemia

237 (81)

18 (6)

 

Alanine aminotransferase increased

229 (78)

35 (12)

 

Aspartate aminotransferase increased

228 (78)

28 (10)

 

Alkaline phosphatase increased

189 (65)

3 (1)

 

Hypocalcemia

179 (61)

15 (5)

 

Hypoalbuminemia

169 (58)

10 (3)

 

Creatine kinase increased

157 (54)

14 (5)

 

Hypophosphatemia

141 (48)

36 (12)

 

Hypokalemia

103 (35)

25 (9)

 

Hyponatremia

93 (32)

36 (12)

 

*Grade 3-5 includes serious, life-threatening and fatal adverse reactions.

XOSPATA Prescribing Information

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

  • Sex: The occurrence of side effects was higher in women.
  • Race: The occurrence of side effects was similar between White and Asian patients. Differences in the occurrence of side effects among other races could not be determined because of the small number of patients of other races.
  • Age: The occurrence of side effects was similar in patients younger and older than 65 years of age.

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

Tables below summarize adverse events during the clinical trials by sex, age and race subgroups in safety population.

Table 6. Subgroup Analyses of Common Adverse Events by Sex

Adverse Event

Men (N=138)

Women (N=154)

Risk
Difference

 

n

%

n

%

Urinary tract infection

0

0

21

14

-14

Stomatitis

27

20

50

32

-13

Hypertransaminasemia

49

36

72

47

-11

Blood alkaline phosphatase increased

17

12

36

23

-11

Hypokalemia

24

17

43

28

-11

Edema

40

29

60

39

-10

Epistaxis

31

22

17

11

11

Table 7. Subgroup Analyses of Common Adverse Events by Race

Adverse Event

White (N=180)

Asian (N=71)

Black (N=16)

Risk Difference*

 

n

%

n

%

n

%

Dizziness

34

19

11

15

7

44

-25

Pneumonia

59

33

17

24

9

56

-23

Hypomagnesaemia

26

14

8

11

6

38

-23

Pericarditis

6

3

3

4

4

25

-22

Encephalopathy

9

5

3

4

4

25

-20

Cough

43

24

20

28

7

44

-20

Hematoma

10

6

1

1

4

25

-19

Nausea

46

26

19

27

7

44

-18

Decreased appetite

24

13

14

20

5

31

-18

Vomiting

36

20

11

15

6

38

-18

Urinary retention

4

2

0

0

3

19

-17

Arrhythmia

27

15

7

10

5

31

-16

Constipation

52

29

21

30

2

13

16

Anemia

83

46

28

39

4

25

21

*Risk difference for Black and White subgroups

Table 8. Subgroup Analyses of Common Adverse Events by Age

 

Adverse Event

Age <65 Years
(N=173)

Age 65 Years
(N=119)

 

Risk
Difference

 

n

%

n

%

Sepsis

18

10

25

21

-11

Hyponatremia

14

8

21

18

-10

Fall

12

7

18

15

-8

Epistaxis

23

13

25

21

-8

Muscular weakness

10

6

15

13

-7

Pneumonia

48

28

41

34

-7

Leukocytosis

4

2

10

8

-6

Hyperglycaemia

19

11

20

17

-6

Diarrhea

57

33

46

39

-6

Anemia

67

39

52

44

-5

Pancreatitis

2

1

7

6

-5

Oedema

56

32

44

37

-5

Retinal haemorrhage

14

8

4

3

5

Mouth haemorrhage

10

6

1

1

5

Hypocalcaemia

32

19

15

13

6

Dizziness

38

22

19

16

6

Hypokalaemia

44

25

23

19

6

Rash

56

32

31

26

6

Hyperbilirubinaemia

23

13

8

7

7

Leukopenia

27

16

10

8

7

Paraesthesia

20

12

5

4

7

Hypertransaminasaemia

77

45

44

37

8

Pain

19

11

4

3

8

Pruritus

19

11

4

3

8

Electrocardiogram QT prolonged

20

12

4

3

8

Nausea

52

30

26

22

8

Headache

42

24

18

15

9

Hypomagnesaemia

32

19

11

9

9

Neutropenia

101

58

58

49

10

Vomiting

43

25

13

11

14

FDA Review

WHO WAS IN THE STUDIES?

Who participated in the clinical trials?

The FDA approved XOSPATA based on evidence from three clinical trials of 292 patients with AML whose disease has come back or has not improved after previous treatment(s).

In Trial 1 (NCT02421939), there were 138 patients and all of them had a certain type of mutation (FLT3-mutation) which was confirmed using an FDA-approved test. The population from this trial provided data that was used to assess the benefit of XOSPATA (called efficacy population). Demographics are presented in Table 10 under more info.

FDA also used data from other two trials where patients were treated with the same dose of XOSPATA as in the efficacy trial. That population (together with population from Trial 1) provided data for assessment of side effects (called safety population). Demographics are presented in the figures below and in Table 9 under MORE INFO.

All trials were conducted in United States, Asia and Europe.

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 trials. In total, 138 men (47%) and 154 women (53%) participated in the clinical trials

FDA Review

Figure 2 and Table 1 below summarize the percentage of patients by race in the clinical trial.

F

Pie chart summarizing the percentage of patients by race in the clinical trials. In total, 180 Whites (62%), 16 Blacks (5%), 71 Asians (24%), and 25 Other (9%), participated in the clinical trials

igure 2. Baseline Demographics by Race

FDA Review

Table 1. Baseline Demographics by Race

Race

Number of Patients

Percentage

White

180

62

Black or African American

16

5

Asian

71

24

Other or missing

25

9

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 trials.  In total, 173 participants were below 65 years old (59%) and 119 participants were 65 and older (41%).

FDA Review

Who participated in the trials?

The table below summarizes demographics of all patients in the three clinical trials combined who received XOSPATA at recommended dose (safety population).

Table 9. Baseline Demographics of Patients in the Clinical Trials (safety population)

Demographic Characteristic

 XOSPATA (N=292)

 

n

%

Sex

Men

138

47%

Women

154

53%

Race

White

180

62%

Asian

71

24%

Black or African American

16

5%

Other or missing

25

9%

Age

<65 years

173

59%

≥65 years

119

41%

≥75 years

39

13%

Ethnicity

Hispanic or Latino

13

5%

Not Hispanic or Latino

279

95%

Region

North America

167

57%

Asia

67

23%

Europe

58

20%

FDA Review

The table below presents demographics of patients who participated in trial used to establish XOPATA efficacy (efficacy population).

Table 10. Baseline Demographics of Patients in the Clinical Trial 1 (efficacy population)

Demographic Characteristic

 XOSPATA (N=138)

 

n

%

Sex

Men

64

46%

Women

74

54%

Race

White

82

60%

Asian

37

27%

Black or African American

10

7%

Other or missing

7

5%

Age Category

<65 years

85

62%

≥65 years

53

38%

≥75 years

19

14%

Ethnicity

Hispanic or Latino

6

4%

Not Hispanic or Latino

127

94%

Region

North America

74

54%

Asia

36

26%

Europe

28

20%

FDA Review

How were the trials designed?

There was one trial that evaluated the benefits of XOSPATA in patients with AML whose disease has come back or has not improved after previous treatment(s). All patients had a certain type of mutation (FLT3-mutation) which was confirmed using an FDA-approved test.

Patients received XOSPATA once a day until disease worsened or unacceptable toxicity.

The benefit of XOSPATA was evaluated 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 the percentage of patients who no longer required transfusions after treatment.

Additional two trials in patients with AML whose disease has come back or has not improved after previous treatment(s) provided data for XOSPATA side effects. All patients in that population (safety population) received XOSPATA at the recommended dose, but not all of them had FLT-3 mutation.

How were the trials designed?

The safety and efficacy of XOSPATA were established in three open-label, randomized, clinical trials of adult patients with relapsed or refractory AML who received XOSPATA orally at dose of 120 mg daily until disease progression or unacceptable toxicity.

The efficacy was established in one of the three trials where all patients had confirmed FLT3 mutation. Efficacy endpoints were the rate of complete remission (CR)/complete remission with partial hematologic recovery (CRh), the duration of CR/CRh (DOR), and the rate of conversion from transfusion dependence to transfusion independence in the trial.

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

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