Drug Trials Snapshots: TURALIO

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 the TURALIO Package Insert for complete information.

TURALIO (pexidartinib)
(tur a' lee oh)
Daiichi Sankyo Inc.
Approval date: August 2, 2019

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DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

TURALIO is a drug used to treat adults with a tumor in the protective layer surrounding the tendons called Tenosynovial Giant Cell Tumor or TGCT. It should only be used in patients when the tumor limits daily activity, and if the tumor cannot be removed by surgery.

How is this drug used?

TURALIO is a capsule taken twice daily on an empty stomach.

What are the benefits of this drug?

Thirty-eight percent of 61 patients who were treated with TURALIO responded to the treatment with complete or partial shrinkage of their tumor. In comparison, none of the 59 patients who were treated with placebo had complete or partial shrinkage of their tumor.

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

The table below shows the Overall Response Rate (ORR) at Week 25 using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria assessed by blinded independent central review (BICR) of MRI scans.

Table 2: Efficacy Results for the Clinical Trial

Efficacy Parameter	TURALIO n=61	Placebo N=59
Overall Response Rate (ORR)a, b
ORR (95% CI)	38% (27%, 50%)	0 (0%, 6%)
Complete Response	15%	0
Partial Response	23%	0
P-valuec	<0.0001
Duration of Response (DOR)b
Range (months)	6.9+, 24.9+	NA

CI: confidence interval; NA: not applicable; SD: standard deviation; LS: least squares; +: denotes ongoing at last assessment
^a Blinded independent central review
^b Data cut-off date January 31, 2018
^c Fisher’s exact test
TURALIO Prescribing information

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

• Sex: TURALIO worked similarly in men and women.
• Race: The majority of patients were White. The number of patients of other races was limited; therefore, differences in how well TURALIO worked among races could not be determined.
• Age: The majority of patients were adults younger than 65 years of age. The number of patients older than 65 years was limited; therefore, differences in how well TURALIO worked between patients younger and older than 65 years of age could not be determined.

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 sex and age group.

Table 3: Overall Response Rate (ORR) at Week 25 in Demographic Subgroups

 

Demographic Parameters		TURALIO (N = 61) # responses/N	ORR (95% CI)
Sex	Men	10/26	38% (22, 57)
	Women	13/35	37% (23, 54)
Age (years)	<65	23/57	40% (29, 53)
	≥65	0/4	0% (0, 5)

ORR: Overall Response Rate; CI: Confidence Interval
FDA Review

What are the possible side effects?

TURALIO can cause serious liver injury which could lead to death. This is the reason that TURALIO is only available through a restricted program called Risk Evaluation and Mitigation Strategy (REMS) program. 

TURALIO may cause harm to a fetus.

The most common side effects of TURALIO are abnormal liver tests, hair color changes, and tiredness. 

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

The table below summarizes adverse reactions that occurred in the clinical trial.

Table 4. Adverse Reactions (> 10% All Grades or >2% Grade > 3) in Patients Receiving TURALIO with a Difference Between Arms of > 5% Compared to Placebo Through Week 25 
 

		TURALIO N=61		Placebo N=59
Adverse Reaction		All Grades (%)	Grade ≥ 3 (%)	All Grades (%)	Grade ≥ 3 (%)
Skin and subcutaneous tissue	Hair color changes	67	0	3.4	0
	Rasha	28	1.6	7	0
	Pruritusb	18	0	3.4	0
General	Fatiguec	64	0	41	0
	Peripheral edemad	20	0	7	0
Eye	Eye edemae	30	1.6	5	0
Nervous system	Dysgeusiaf	26	0	1.7	0
	Neuropathyg	10	0	5	0
Gastrointestinal	Vomiting	20	1.6	5	0
	Constipation	12	0	5	0
Metabolism and nutrition	Decreased appetite	16	0	10	0
Vascular	Hypertension	15	4.9	10	0

^a Rash includes rash, maculo-papular rash, rash pruritic, urticaria, erythema, dermatitis acneiform, dermatitis allergic.
^b Pruritis includes pruritus, pruritus generalized
^c Fatigue includes fatigue, asthenia, malaise.
^d Peripheral edema includes face edema, localized edema, edema peripheral, peripheral swelling
^e Eye edema includes periorbital edema, eye edema, eyelid edema, papilledema.
^f Dysgeusia includes dysgeusia, ageusia
^g Neuropathy includes neuropathy peripheral, paresthesia, hypoesthesia, burning sensation.

The table below summarizes the hepatic laboratory abnormalities during the trial.

Table 5: Hepatic Laboratory Abnormalities in Patients Receiving TURALIO with a Difference Between Arms of >5% Compared to Placebo Through Week 25

		TURALIOa			Placeboa
Laboratory Abnormalityb		Grade 1 (%)	Grade 2 (%)	Grade ≥ 3 (%)	Grade 1 (%)	Grade 2  (%)	Grade ≥ 3 (%)
Liver Tests	Increased AST	61	15	12	15	0	0
	Increased ALT	31	13	20	22	0	0
	Increased ALP	31	3.3	4.9	1.7	0	0
	Increased bilirubin	3.3	3.3	3.3	0	0	0

ALT = alanine aminotransferase; AST = aspartate aminotransferase; ALP = alkaline phosphatase
^a Each test incidence is based on the number of patients who had both a baseline and at least one on-study measurement TURALIO (n=61) and placebo (n=59)
^b Graded per NCI CTCAE v 4.03
TURALIO Prescribing Information

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

• Sex: The occurrence of side effects was similar between men and women.
• Race: The majority of patients were White. The number of patients of other races was limited; therefore, differences in the occurrence of side effects among races could not be determined.
• Age: Most patients were adults younger than 65 years of age. The number of patients older than 65 years of age was limited; therefore, differences in the occurrence of side effects between patients younger and older than 65 years of age could not be determined.

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

The tables below summarize adverse events by subgroup.

Table 6: Adverse Events by Sex

	TURALIO (n = 61)		Placebo (n = 59)
Adverse Event	Men N = 26 n (%)	Women N = 35 n (%)	Men N= 23 n (%)	Women N= 36 n (%)
Any TEAE	25 (96)	35 (100)	22 (96)	33 (92)
Any SAE	1 (3.8)	7 (11)	0	1 (2.8)

TEAE: treatment emergent adverse event; SAE: serious adverse event
FDA Review

Table 7: Adverse Events by Race

	TURALIO (n = 61)		Placebo (n = 59)
Adverse Event	White (N = 52) n (%)	Other N = 9 n (%)	White N= 54 n (%)	Other N= 5 n (%)
Any TEAE	51 (98)	9 (100)	50 (93)	5 (100)
Any SAE	6 (12)	2 (17)	1 (1.9)	0

TEAE: treatment emergent adverse event; SAE: serious adverse event
FDA Review

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved TURALIO based on evidence from 1 clinical trial (NCT02371369) of 120 patients with Tenosynovial Giant Cell Tumor or TGCT. The trial was conducted in Australia, Canada, Europe, and the United States.

Figure 1 summarizes how many men and women were in the clinical trial used to evaluate efficacy

Figure 1. Baseline Demographics by Sex

FDA Review

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

Figure 2. Baseline Demographics by Race

FDA Review

Table 1. Demographics of Trials by Race

Race	Number of Patients	Percentage of Patients
White	106	88%
Black or African-American	4	3%
Asian	3	3%
Native Hawaiian or Other Pacific Islander	4	3%
American Indian or Alaskan Native	2	2%
Other	1	1%

FDA Review

Figure 3 summarizes the percentage of patients by age group in the clinical trial.

Figure 3. Baseline Demographics by Age

FDA Review

Who participated in the trials?

The table below summarizes baseline demographics for the clinical trial.

Table 8: Baseline Demographics for the Clinical Trial

		TURALIO N = 61 n (%)	Placebo N = 59 N (%)
Sex	Men	26 (43)	23 (39)
	Women	35 (57)	36 (61)
Race	White	52 (85)	54 (92)
	Black	3 (4.9)	1 (1.7)
	Asian	1 (1.6)	2 (3.4)
	Native Hawaiian or Other Pacific Islander	2 (3.2)	2 (3.4)
	American Indian or Alaskan Native	2 (3.2)	0
	Other	1 (1.6)	0
Age	18 to < 65 years	57 (93)	56 (95)
	≥ 65 years	4 (7)	3 (5)
Ethnicity	Not Hispanic or Latino	49 (80)	50 (86)
	Hispanic/ Latino	9 (15)	8 (14)
	Unknown	3 (4.9)	1 (1.7)
Region	United States	23 (38)	22(37)
	Rest of World	38 (62)	37 (63)

FDA Review

How were the trials designed?

The benefits and side effects of TURALIO were evaluated in one clinical trial that enrolled adult patients with TGCT. All patients had limitations of daily activities due to the tumor and could not have the tumor removed by surgery. Patients received TURALIO or placebo twice a day until the disease worsened or they could not tolerate the side effects. Neither the patients nor the healthcare providers knew which treatment was being given for 24 weeks. After week 24, patients who received treatment with TURALIO could continue treatment and patients who received placebo could be treated with TURALIO. The benefit of TURALIO was evaluated at Week 25 by counting the patients who experienced partial or complete tumor shrinkage. The size of the tumor was evaluated by an imaging technique called magnetic resonance imaging (MRI).

How were the trials designed?

The efficacy and safety of TURALIO was demonstrated in a multicenter, randomized, double-blind, placebo-controlled trial in patients with symptomatic TGCT also referred to as giant cell tumor of the tendon sheath (GCT-TS) or pigmented villonodular synovitis (PVNS). All patients had severe morbidity or functional limitations, and their tumors were not amenable to improvement with surgery. Supportive medications including analgesics were permitted. The trial had 2 phases, a treatment and an open label extension phase. During the treatment phase, patients were randomized 1:1 to either TURALIO 400mg in the morning and 600mg in the evening for two weeks, followed by 400 mg twice daily or placebo for a total of 24 weeks. TURALIO was continued until unacceptable toxicity or disease progression. Patients randomized to receive placebo were permitted to start TURALIO 400 mg twice daily at Week 25.

The primary endpoint was overall response rate at Week 25 using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria assessed by blinded independent central review (BICR) of MRI scans.

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.

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