ENLIVEN Clinical Trial

The efficacy of TURALIOTM (pexidartinib) was evaluated in a multicenter, randomized, double-blind, placebo-controlled phase 3 study (ENLIVEN).1,2

ENLIVEN patients: Symptomatic TGCT (also referred to as giant cell tumor of the tendon sheath or pigmented villonodular synovitis) for whom surgical removal of the tumor would be associated with worsening functional limitation or severe morbidity.1

ENLIVEN study design1,2,a

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a ENLIVEN excluded patients with alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin >1.5 × upper limit of normal (ULN), as well as those with known active or chronic infection with hepatitis B or C virus or human immunodeficiency virus. 1

b The FDA-approved dose of TURALIO is 400 mg twice daily. 1

c Patients receiving TURALIO in part 1 continued with their same dose in part 2. 2

ENLIVEN study endpoints1,2

endpoints endpoints
a Secondary endpoints were assessed at week 25, with the exception of DOR.1,2

ENLIVEN study baseline characteristics of patients1

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TGCT, tenosynovial giant cell tumor.
Of the randomized patients, 47% had not had prior surgery
and were not eligible for surgery for TGCT.

A significantly greater number of patients receiving TURALIO demonstrated a reduction in tumor size by RECIST compared to patients treated with placebo1

Primary endpoint: ORR by RECIST at week 251,3,a

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BICR, blinded independent central review; CI, confidence interval; CR, complete response; ORR, overall response rate; PR, partial response; RECIST, Response Evaluation Criteria In Solid Tumors.

a ORR was determined by BICR.1

b For ORR, 95% CI was 27%-50% for TURALIO-treated patients and 0%-6% for placebo. Data cut-off date of January 31, 2018.1

c Fisher’s exact test.1

RECIST v1.1
  • This linear measurement calculates tumor size by measuring the largest diameter of the tumor 3
  • RECIST was used to assess the primary endpoint of ORR at
    week 251
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Black arrows are representations only, not exact measurements. Grey dotted lines represent the synovial cavity. Yellow areas represent tumor size.

ORR by RECIST was 38% in TURALIO-treated patients(95% CI, 26%-50%) and 0% in placebo-treated patients (95% CI, 0%-6%) at week 25.1

CI, confidence interval; ORR, overall response rate.

79% of patients received TURALIO for 6 months or longer and 66% for >1 year.1
DOR for responders to TURALIO1,a :

Range (months): 6.9+, 24.9+

79% of patients received
TURALIO for 6 months or longer
and 66% for >1 year.1
DOR for responders to TURALIO1,a :

Range (months): 6.9+, 24.9+

DOR, duration of response.
a Data cutoff date of January 31, 2018.
“+” Denotes ongoing at last assessment.
A significantly greater number of patients receiving TURALIO demonstrated tumor reduction as assessed by Tumor Volume Score (TVS) compared to patients treated with placebo1

Secondary endpoint: ORR by TVS at week 251,4,a

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CI, confidence interval; ORR, overall response rate; TVS, Tumor Volume Score.

a For ORR, 95% CI was 43%-67% in TURALIO-treated patients.1

TVS
  • Because of the irregular shape and poor contrast between the tumor and its surroundings, linear measurement of tumor response in TGCT is challenging4,5
  • TVS was defined in ENLIVEN as the estimated volume of the maximally distended synovial cavity or tendon sheath involved, measured in 10% increments1
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Black arrows are representations only, not exact measurements. Grey dotted lines represent the synovial cavity. Yellow areas represent tumor size.

Range of motion endpoint

TURALIO significantly improved ROM of the affected joint compared with placebo, assessed at week 25 as mean percentage change from baseline1
Statistically significant improvement in mean change from baseline in ROM at
week 25 was demonstrated in patients randomized to TURALIO compared with placebo.

Change from baseline in ROM at week 25 for ENLIVEN1,a

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ROM, range of motion.
  • a Results were excluded for 1 patient with missing baseline and 31 patients with a missing ROM assessment at week 25. Assessments were performed by a third-party clinical assessor using a goniometer.
  • bPercent of normal reference range for the affected joint.
  • cTumor response by RECIST v1.1.

Safety information

Adverse reactions1

  • Serious adverse reactions were reported in 13% of patients who received TURALIO, most frequently* including abnormal liver tests (3.3%) and hepatotoxicity (3.3%)
  • Permanent discontinuation due to adverse reactions occurred in 13% of patients who received TURALIO, most frequently* due to increased ALT (4.9%), increased AST (4.9%), and hepatotoxicity (3.3%)
  • The most common adverse reactions (>20%) were increased lactate dehydrogenase (LDH), increased AST, hair color changes, fatigue, increased ALT, decreased neutrophils, increased cholesterol, increased alkaline phosphatase (ALP), decreased lymphocytes, eye edema, decreased hemoglobin, rash, dysgeusia, and decreased phosphate

* Occurring in >1 patient.

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
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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, paraesthesia, hypoaesthesia, burning sensation.

Laboratory abnormalities

Hepatic laboratory abnormalities (≥10% all grades or >2% grade ≥3) worsening from baseline in patients receiving TURALIO with a difference between arms of >5% compared to placebo through week 251
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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.

b Graded per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v 4.03.

Other laboratory abnormalities worsening from baseline (≥10% all grades or >2% of grade ≥3) in patients receiving TURALIO with a difference between arms of >5% compared to placebo through week 251
lab-table lab-table

LDH, lactate dehydrogenase.

a Each test incidence is based on the number of patients who had both a baseline and at least one on-study measurement.

b Graded per NCI CTCAE v 4.03 except for LDH.

c LDH: Grade 1: >ULN to ≤2.5 x ULN; Grade 2: >2.5 to ≤5 x ULN; Grade 3: >5 to ≤20 x ULN; Grade 4: >20 x ULN.

Other clinically relevant adverse reactions1

Clinically relevant adverse reactions occurring in <10% of patients were:

  • Eye: blurred vision, photophobia, diplopia, reduced visual acuity
  • Gastrointestinal: dry mouth, stomatitis, mouth ulceration
  • General: pyrexia
  • Hepatobiliary: cholangitis, hepatotoxicity, liver disorder
  • Neurological: cognitive disorders (memory impairment, amnesia, confusional state, disturbance in attention, attention deficit/hyperactivity disorder)
  • Skin and subcutaneous tissue: alopecia, skin pigment changes (hypopigmentation, depigmentation, discoloration, hyperpigmentation)

Prescribing TURALIO Due to the risk of hepatotoxicity, TURALIO is available only through a restricted program called TURALIO REMS. In order to prescribe TURALIO, a healthcare provider must become certified.