Drug Trial Snapshot: DAURISMO

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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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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 DAURISMO Prescribing Information for complete information.

DAURISMO (glasdegib)
DOOR-is-moe
Pfizer, Inc.
Approval date:November 21, 2018

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DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

DAURISMO is used to treat adults with newly-diagnosed acute myeloid leukemia (AML).

It is to be used in patients who

• are 75 years of age or older, or
• have other medical conditions that prevent the use of standard chemotherapy.

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?

DAURISMO is a tablet used once a day together with another drug (cytarabine) at low dose.

What are the benefits of this drug?

In the trial, patients treated with DAURISMO together with low dose cytarabine lived about 8.3 months in comparison to patients treated with cytarabine alone who lived about 4.3 months.

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

The table below summarizes efficacy results established on the overall survival (OS) from the date of randomization to death from any cause.

Table 2. Efficacy Results

Endpoint	DAURISMO With Low-Dose Cytarabine	Low-Dose Cytarabine Alone
OS	N=77	N=38
Median survival, months (95% CI)	8.3 (4.4, 12.2)	4.3 (1.9, 5.7)
Hazard ratio (95% CI)a	0.46 (0.30, 0.71)
p-valueb	0.0002
CR	N=14	N=1
CR rate (in %, 95% CI)	18.2 (10.3, 28.6)	2.6 (0.1, 13.8)

Abbreviations: AML = acute myeloid leukemia; N = number of patients; OS = overall survival; CI = confidence interval; CR = complete response.

^a. Hazard ratio (DAURISMO with low-dose cytarabine/low-dose cytarabine alone) based on the Cox Proportional hazards model stratified by cytogenetic risk.

^b. 1-sided p-value from log-rank test stratified by cytogenetic risk.

DAURISMO Prescribing Information

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

• Sex: DAURISMO worked similarly in men and women.
• Race: Most of the patients were White. Differences in how well DAURISMO worked among races could not be determined because of the small number of patients of other races.
• Age: DAURISMO worked similarly in patients younger and older than 75 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 Overall Survival by Sex, Race, and Age

Subgroup	DAURISMO +Low-Dose Cytarabine (N=77)	Low-Lose Cytarabine (N=38)	Hazard Ratio (95%CI)
Sex
Men	59	23	0.42 (0.25,0.72)
Women	18	15	0.48 (0.22,1.06)
Race
White	75	38	0.46 (0.3,0.72)
All Other	2	0	-
Age Group
<75 years	30	15	0.27 (0.13,0.57)
≥ 75 years	47	23	0.59 (0.34,1.01)

Adapted from FDA Review

What are the possible side effects?

DAURISMO is harmful to the unborn child. Both men and women should use effective contraception during treatment with DAURISMO and for at least 30 days after the last dose.

The most common side effects of DAURISMO are anemia, fatigue, bleeding, low blood cell counts, fever, bone and muscle pains, nausea, swelling, shortness of breath, decreased appetite, changes in taste, pain or sores in your mouth or throat, constipation, and rash.

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.

Table 4. Adverse Reactions Occurring in ≥ 10% of Patients^a,b Within the First 90 Days of Therapy

Body System	Adverse Reactions	DAURISMO with Low-Dose Cytarabine N=84		Low-Dose Cytarabine N=41
		All Grades %	Grade ≥ 3 %	All Grades %	Grade ≥ 3 %
Blood and lymphatic system disorder	Anemia Hemorrhagec Febrile neutropenia Thrombocytopenia	43 36 31 30	41 6 31 30	42 42 22 27		37 12 22 24
General disorders and administration site conditions	Fatigued Edemae Mucositisf Pyrexia Chest paing	36 30 21 18 12	14 0 1 1 1	32 20 12 22 2		7 2 0 2 0
Musculoskeletal and connective tissue disorders	Musculoskeletal painh Muscle spasmI	30 15	2 0	17 5		2 0
Gastrointestinal disorders	Nausea Constipation Abdominal painj Diarrheak Vomiting	29 20 19 18 18	1 1 0 4 2	12 12 12 22 10		2 0 0 0 2
Respiratory thoracic and mediastinal disorders	Dyspneal Coughm	23 18	11 0	24 15		7 2
Metabolism and nutrition disorders	Decrease appetite	21	1	7		2
Nervous system disorders	Dysgeusian Dizziness Headache	21 18 12	0 1 0	2 7 10		0 0 2
Skin and subcutaneous tissue disorders	Rasho	20	2	7		2
Infection and infestations	Pneumoniap	19	15	24		22
Investigations	Hyponatremia Platelet count decreased Weight decreased White blood cell count decreased	11 15 13 11	6 15 0 11	0 10 2 5		0 10 0 2
Cardiac disorders	Atrial arrhythmiaq	13	4	7		2
Renal and urinary disorders	Renal insufficiencyr	19	5	10		0

Abbreviations: N = number of patients.
Preferred terms were retrieved by applying the Medical Dictionary for Regulatory Activities (MedDRA) version 19.1.
Trial used National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Adverse reactions include events that commenced within 28 days after the last treatment dose.
a. Adverse reactions with ≥10% incidence in the DAURISMO with low-dose cytarabine arm or the low-dose cytarabine arm are included.
b. No Grade 5 events in the DAURISMO with low-dose cytarabine or low-dose cytarabine alone arm.
c. Hemorrhage includes petechiae, epistaxis, hematoma, contusion, rectal hemorrhage, anal hemorrhage, ecchymosis, gingival bleeding, hematuria, mouth hemorrhage, purpura, cerebral hemorrhage, eye contusion, eye hemorrhage, gastric hemorrhage, gastrointestinal hemorrhage, hematemesis, hemoptysis, hemorrhage, implant site hematoma, injection site bruising, retroperitoneal hematoma, thrombotic thrombocytopenic purpura, tracheal hemorrhage, conjunctival hemorrhage, disseminated intravascular coagulation, eyelid hematoma, hematochezia, hemorrhage intracranial, hemorrhoidal hemorrhage, lower gastrointestinal hemorrhage, retinal hemorrhage, and subdural hematoma.
d. Fatigue includes asthenia and fatigue.
e. Edema includes edema peripheral, edema, fluid overload, fluid retention, and swelling face.
f. Mucositis includes mucosal inflammation, oropharyngeal pain, stomatitis, anal ulcer, gingival pain, laryngeal inflammation, esophagitis, oral pain, aphthous ulcer, mouth ulceration, and pharyngeal inflammation.
g. Chest pain includes chest pain and non-cardiac chest pain.
h. Musculoskeletal pain includes pain in extremity, arthralgia, back pain, myalgia, musculoskeletal pain, musculoskeletal chest pain, neck pain, and bone pain.
i. Muscle spasms includes muscle spasms and muscle tightness.
j. Abdominal pain includes abdominal pain, abdominal pain upper, and abdominal pain lower.
k. Diarrhea includes diarrhea, colitis, and gastroenteritis.
l. Dyspnea includes dyspnea, hypoxia, bronchospasm, and respiratory failure.
m. Cough includes cough and productive cough.
n. Dysgeusia includes dysgeusia and ageusia.
o. Rash includes rash, pruritus, erythema, skin ulcer, rash maculo-papular, and rash pruritic.
p. Pneumonia includes pneumonia, pneumonia aspiration, and lung infection.
q. Atrial arrhythmia includes atrial fibrillation, bradycardia, tachycardia, and sinus tachycardia.
r. Renal insufficiency includes acute kidney injury, blood creatinine increased, oliguria, and renal failure.

DAURISMO Prescribing Information

Table 5. Selected Laboratory Abnormalities (≥ 15% )^a Within the First 90 Days of Therapy

Laboratory Abnormality	DAURISMO with Low-Dose Cytarabine			Low-Dose Cytarabine
	N	All Grades %	Grade 3 or 4* %	N	All Grades %	Grade 3 or 4* %
Creatinine increased	81	96	1	40	80	5
Hyponatremia	81	54	7	39	41	8
Hypomagnesemia	81	33	0	39	23	0
AST increased	80	28	1	40	23	0
Blood bilirubin increased	80	25	4	39	33	3
ALT increased	80	24	0	40	28	3
Alkaline phosphatase increased	80	23	0	40	28	3
Hyperkalemia	81	16	1	40	8	3
CPK increased	38	16	0	17	6	0
Hypokalemia	81	15	0	40	23	0

Abbreviations: N = number of patients; AST = aspartate aminotransferase; ALT = alanine aminotransferase; CPK = creatinine phosphokinase.
BRIGHT AML 1003 used National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
* Grade 1 is mild, Grade 2 is moderate, Grade 3 is severe, Grade 4 is life-threatening.
a. Maximum severity based on the number of patients with available on-study laboratory data.

DAURISMO 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 of other races.
• Age: The occurrence of side effects was similar between patients younger and older than 75 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 (AEs) during the clinical trials by sex, age and race subgroup. These analyses were exploratory and therefore should be interpreted with caution.

Table 6. Subgroup Analyses of Adverse Events by Sex

Adverse Events	DAURISMO + Low-Dose Cytarabine		Low Dose-Cytarabine
	Men (N=66)	Women (N=16)	Men (N=24)	Women (N=17)
Any AEs, n (%)	66 (100.0)	18 (100.0)	24 (100.0)	17 (100.0)
Febrile neutropenia	23 (34.8)	7 (38.9)	6 (25.0)	4 (23.5)
Diarrhea	15 (22.7)	8 (44.4)	6 (25.0)	3 (17.6)
Anemia	28 (42.4)	10 (55.6)	8 (33.3)	9 (52.9)
Nausea	19 (28.8)	11 (61.1)	1 (4.2)	4 (23.5)

Table 7a. Subgroup Analyses of Adverse Events by Age Group (<65 years v. ≥65 years)

Adverse Events	DAURISMO + Low Dose Cytarabine		Low -Dose Cytarabine
	<65 years (N=2)	≥65 years (N=82)	<65 years (N=1)	≥65 years (N=40)
Any AEs, n (%)	2 (100.0)	82 (100.0)	1 (100.0)	40 (100.0)
Nausea	1 (50.0)	29 (35.4)	0 (0.0)	5 (12.5)
Diarrhea	1 (50.0)	22 (26.8)	1 (100.0)	8 (20.0)
Febrile neutropenia	0 (0.0)	30 (36.6)	0 (0.0)	10 (25.0)
Anemia	1 (50.0)	37 (45.1)	0 (0.0)	17 (42.5)
Constipation	1 (50.0)	20 (24.4)	0 (0.0)	6 (15.0)

Table 7b. Subgroup Analyses of Adverse Events by Age Group (<75 years v. ≥75 years)

Adverse Events	DAURISMO + Low-Dose Cytarabine		Low-Dose Cytarabine
	<75 years (N=34)	≥75 Years (N=50)	<75 Years (N=17)	≥75 Years (N=24)
Any AEs, n (%)	34 (100.0)	50 (100.0)	17 (100.0)	24 (100.0)
Febrile neutropenia	12 (35.3)	18 (36.0)	5 (29.4)	5 (20.8)
Anemia	18 (52.9)	20 (40.0)	7 (41.2)	10 (41.7)
Nausea	14 (41.2)	16 (32.0)	3 (17.6)	2 (8.3)
Constipation	5 (14.7)	16 (32.0)	2 (11.8)	4 (16.7)
Decreased appetite	8 (23.5)	20 (40.0)	1 (5.9)	4 (16.7)

Table 8. Analyses of Adverse Events by Race

Adverse Events	DAURISMO + Low Dose-Cytarabine			Low-Dose Cytarabine
	White (N=81)	Black or African American (N=1)	Asian (N=2)	White (N=41)
Any AEs, n (%)	81 (100.0)	1 (100.0)	2 (100.0)	41 (100.0)
Diarrhea	22 (27.2)	1 (100.0)	0 (0.0)	9 (22.0)
Febrile neutropenia	29 (35.8)	0 (0.0)	1 (50.0)	10 (24.4)
Nausea	29 (35.8)	1 (100.0)	0 (0.0)	5 (12.2)
Anemia	37 (45.7)	1 (100.0)	0 (0.0)	17 (41.5)
Pyrexia	21 (25.9)	1 (100.0)	1 (50.0)	9 (22.0)
Constipation	20 (24.7)	0 (0.0)	1 (50.0)	6 (14.6)
Fatigue	24 (29.6)	1 (100.0)	1 (50.0)	8 (19.5)

Adapted from Clinical trial report

WHO WAS IN THE STUDIES?

Who participated in the clinical trials?

The FDA approved DAURISMO based on evidence from one clinical trial (NCT01546038) of 125 patients treated with DAURISMO. One hundred fifteen patients assigned to treatment with DAURISMO had newly-diagnosed AML.

The trial was conducted in United States, Canada and Europe.

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

Figure 1. Baseline Demographics by Sex

Daurismo_Figure1

FDA Review

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

Figure 2. Baseline Demographics by Race

 

Daurismo_Figure 2

FDA Review

Table 1. Baseline Demographics by Race

Race	Number of Patients	Percentage
White	122	98
Asian	2	2
Black or African American	1	less than 1

FDA Review

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

Figure 3. Baseline Demographics by Age

 

Baseline Demographics by Age

FDA Review

Who participated in the trials?

The table below summarizes demographics of all patients enrolled in the clinical trial who received DAURISMO (safety population).

Table 9. Baseline Demographics (safety population)

Demographic Category	DAURISMO with Low-Dose Cytarabine N=84	Low -Dose Cytarabine N=41	TOTAL N=125
Sex, n (%)
Men	66 (79)	24 (59)	90 (72)
Women	18 (21)	17 (41)	35 (28)
Race, n (%)
White	81 (96)	41 (100)	122 (98)
Asian	2 (2)	0	2 (2)
Black or African American	1 (1)	0	1 (<1)
Age (years)
Mean	76	75	76
Median	77	76	77
Min, Max	63, 92	58, 83	58, 92
Age Group (years)
<65 years	2 (2)	1(2)	3 (2)
≥65 years	82 (98)	40 (98)	122 (98)
Ethnicity, n (%)
Unknown	84 (100)	41 (100)	125 (100)
Region, n (%)
United States	23 (27)	6 (15)	29 (23)
Canada	8 (10)	1 (2)	9 (7)
Europe	53 (63)	34 (83)	87 (70)

FDA Review 

How were the trials designed?

There was one trial that evaluated the benefit and side effects of DAURISMO in patients with newly-diagnosed with AML.

Patients received DAURISMO once daily in combination with low-dose cytarabine or low-dose cytarabine alone up to 1 year (12 cycles) or until disease worsened or unacceptable toxicity. Both patients and heath care providers knew which treatment was given.

The benefit of DAURISMO in combination with low-dose cytarabine was evaluated in patients with newly diagnosed AML by measuring how long the patients lived (this is called overall survival or OS) in comparison to patients who received low-dose cytarabine alone.

How were the trials designed?

The safety and efficacy of DAURISMO in combination with low-dose cytarabine was evaluated in a multicenter, open label, randomized trial that included patients 55 years or older with newly-diagnosed AML

One hundred and twenty-five patients received DAURISMO orally at dose of 100 mg daily with low dose cytarabine 20 mg subcutaneously twice daily on days 1 to 10 of a 28-day cycle or low-dose cytarabine alone in 28-day cycles until disease progression or unacceptable toxicity.

The efficacy was established on the basis of overall survival (OS) from the date of randomization to death from any cause.

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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