Drugs

Drug Trials Snapshots: UNITUXIN

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 UNITUXIN Prescribing Information for complete information.

UNITUXIN (dinutuximab)
(yoo-ni-TUX-in)
United Therapeutics Corporation
Approval date: Approval date: March 10, 2015


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

UNITUXIN is a drug that is used to treat children with high-risk neuroblastoma, a rare and serious cancer that develops from nerve cells and most often occurs in young children. UNITUXIN is used to treat children whose tumor has shrunk following other treatments, which include a combination of chemotherapy, surgery, and radiation.

How is this drug used?

UNITUXIN is given as a slow infusion (taking 10-20 hours) into a vein. Three other drugs, 13-cis-retinoic acid (RA), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2), are given in a specific order along with UNITUXIN.

What are the benefits of this drug?

In the trial that supported the FDA approval of UNITUXIN combined with IL-2, GM-CSF, and RA, 63% of patients who received the UNITUXIN combination were alive and had no growth or recurrence of their tumor three years after enrollment, compared to 46% of patients who received RA alone.

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

The table below summarizes efficacy results for the trial.

Table 2. Efficacy Results for the Clinical Trial (Intent to Treat Population)

Efficacy ParameterUNITUXIN/RA arm
N=113
RA arm
N=113
EFSNumber of Events (%)33 (29)50 (44)
Median (95% CI) (years)NR (3.4, NR)1.9 (1.3, NR)
Hazard Ratio (95 % CI)0.57 (0.37, 0.89)
p-value (log-rank test)10.01
OS2Number of Events31 (27)48 (42)
Median (95% CI) (years)NR (7.5, NR)NR (3.9, NR)
Hazard Ratio (95 % CI)0.58 (0.37, 0.91)

RA=13-cis-retinoic acid; NR=not reached; EFS= event-free survival; OS= overall survival
1 Compared to the allocated alpha of 0.01 pre-specified for the seventh interim analysis of EFS
2 Based on an additional three years of follow up after the seventh interim analysis of EFS
Source: UNITUXIN Package Insert, Section 14, Table 10

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

Subgroup analyses were conducted for sex, race and age.

  • Sex: UNITUXIN was similarly effective in boys and girls.
  • Race: The majority of patients were White. Therefore, differences in response to UNITUXIN could not be determined.
  • Age: The majority of patients were 2 to 11 years old. Therefore, differences in response to UNITUXIN among patients younger than 2 and older than 11 years could not be determined.

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

Table 3. Subgroup Analysis of Event-Free Survival

Demographic SubgroupUNITUXIN/RARAHazard Ratio (95% CI)
Number of EFS events/n
Sex
Male21/7128/640.6 (0.4, 1.1)
Female12/4222/490.5 (0.2, 1.0)
Dichotomized Age
<18 months0/42/40
≥18 months33/10948/1090.6 (0.4, 0.9)
Age Category
Infant Toddler (Age <2)1/125/180.3 (0, 2.5)
Child (2 to 11 years)32/9744/940.6 (0.4, 0.9)
Adolescent (12 to 17 years)0/41/10
Race
White26/9539/900.6 (0.3, 0.9)
Black or African American2/85/80.3 (0.1, 1.4)
Asian1/22/40.5 (0, 6.6)
Native Hawaiian or Other Pacific Islander0/01/2NA
Multiple0/11/20
Other0/10/0NA
Unknown4/62/72.5 (0.5, 14.0)

Source: From Clinical Review

What are the possible side effects?

The most common side effects of UNITUXIN were:

  • severe pain
  • fever
  • low platelet counts which can lead to bleeding
  • low numbers of white blood cells which help fight infection
  • reactions occurring during or shortly after the infusion of UNITUXIN, including itching and flushing, hives, swelling of the face and lips, and breathing problems
  • low blood pressure

Serious side effects were:

  • severe pain and possible nerve damage due to the irritation of nerve cells
  • life-threatening reactions related to the infusion of UNITUXIN through a vein, including swelling of the upper airways, difficulty breathing, and low blood pressure, that can occur during or shortly after the infusion is done
  • leakage of fluid from blood vessels causing swelling and low blood pressure
  • infections
  • eye problems that can result in loss of sight
  • abnormal blood levels of sodium, potassium, and calcium
  • low blood cell counts  

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

The table below summarizes adverse reactions in the clinical trial.

Table 4. Percentage of Patients with Adverse Reactions Occurring in at least 10% of the Patients in the Unituxin/RA Group in the Clinical Trial (Safety Population)

Adverse ReactionUNITUXIN/RA
N=134*
(%)
RA
N=106
(%)
Pain8516
Pyrexia7227
Thrombocytopenia6643
Lymphopenia6236
Infusion Reactions609
Hypotension603
Hyponatremia5812
Increased alanine aminotransferase5631
Anemia5122
Vomiting4619
Diarrhea4315
Hypokalemia434
Capillary leak syndrome401
Neutropenia3916
Urticaria373
Hypoalbuminemia333
Increased aspartate aminotransferase287
Hypocalcemia270
Hypoxia242
Hypophosphatemia203
Tachycardia191
Hyperglycemia184
Sepsis189
Hemorrhage176
Edema170
Hypertriglyceridemia1611
Device related infection1611
Proteinuria163
Increased serum creatinine156
Decreased appetite155
Hypertension147
Peripheral neuropathy136
Hypomagnesemia121
Increased weight100
Nausea103

* Unituxin safety population includes 109 randomized patients and 25 patients with biopsy-proven residual disease who were non-randomly assigned to receive Unituxin
Source: Extracted from UNITUXIN Package Insert, Section 6, Table 5

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

Subgroup analyses were conducted for sex, race and age.

  • Sex: The risk of overall side effects was similar in males and females.
  • Race: The majority of patients were White. Therefore, differences in side effects among races could not be determined.
  • Age: The majority of patients were 2 to 11 years old. Therefore, differences in side effects among patients younger than 2 and older than 11 years could not be determined.

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

The following table summarizes adverse reactions by System Organ Class (Body System) in males and females in the pivotal trial.

Table 5. Subgroup Analysis of Adverse Reactions in Males and Females by Body System (Safety Population)

Body SystemMale
N=139
Female
N=101
UNITUXIN/RA
n=80*
n (%)
RA
n=59
n (%)
UNITUXIN/RA
n=54*
n (%)
RA
n=47
n (%)
Blood and Lymphatic System Disorders62 (78)30 (51)44 (81)24 (51)
Cardiac Disorders17 (21)1 (2)10 (19)1 (2)
Gastrointestinal Disorders46 (57)21 (36)34 (63)14 (30)
General disorders and Administration Site Conditions71 (89)20 (34)52 (96)14 (30)
Immune System Disorders45 (56)5 (8)35 (65)4 (9)
Infections and Infestations41 (51)24 (41)33 (61)23 (49)
Investigations59 (74)35 (59)47 (87)22 (47)
Metabolism and Nutrition Disorders60 (75)14 (24)45 (83)15 (32)
Nervous System Disorders19 (24)6 (10)13 (24)6 (13)
Renal and Urinary Disorders20 (25)1 (2)17 (31)6 (13)
Respiratory, Thoracic, and Mediastinal Disorders25 (31)6 (10)27 (50)1 (2)
Skin and Subcutaneous Tissue Disorders37 (46)16 (27)30 (56)8 (17)
Vascular Disorders54 (68)5 (8)46 (85)4 (9)

Source: From Company Submission
* Unituxin safety population includes 109 randomized patients and 25 patients with biopsy-proven residual disease who were non-randomly assigned to receive Unituxin

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved UNITUXIN based on a clinical trial of 226 children with high-risk neuroblastoma who already received treatment for their disease and had shrinkage of their tumor.

The trial was conducted at 90 centers in the United States, Canada, and Australia.  

Figure 1 summarizes how many boys and girls were enrolled in the clinical trial.

Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many men and women were enrolled in the UNITUXIN clinical trial.  In total, 135 men (60%) and 91 women (40%) participated in the clinical trial.

Source: From Clinical Reviewer

Figure 2 summarizes how many patients by race were in the clinical trial.

Figure 2. Baseline Demographics by Race

Bar chart summarizing the percentage of patients by race enrolled in the UNITUXIN clinical trial. In total, 185 White (81.9%), 16 Black (7.1%), 6 Asian (2.7%), 2 Native Hawaiian or Pacific Islander (0.9%), 3 identified as multiple races (1.3%), 1 identified as other (0.4%), and 13 where race data was missing (5.8%) participated in the clinical trials.

Source: From Clinical Reviewer

Table 1. Baseline Demographics by Race

RaceNumber of PatientsPercentage (%)
White18581.9
Black or African American167.1
Asian62.7
Native Hawaiian or Other Pacific Islander20.9
Multiple31.3
Other10.4
Unknown135.8

Source: From Clinical Reviewer

The figure below summarizes the age of patients in the clinical trial.

Figure 3. Baseline Demographics by Age

 Pie chart summarizing how many individuals of certain age groups were enrolled in the UNITUXIN clinical trial.  In total, 30 were less than two (13%), 191 were between 2 and 11 years (85%), and 5 were over the age of 12 but under 17 (2%).

Source: From Clinical Reviewer

Who participated in the trials?

The table below summarizes baseline demographics for the trial that supported the approval of UNITUXIN.

Table 6. Baseline Demographics (Intent to Treat Population)

Demographic ParameterUNITUXIN/RA
N=113
RA
N=113
Sex n (%)
Male71 (63)64 (57)
Female42 (37)49 (43)
Age at Enrollment (years)
Mean (SD)4.3 (2.5)4.0 (2.1)
Median3.93.5
Min, Max0.9, 15.30.9, 13.3
Dichotomized Age n (%)
<18 months4 (4)4 (4)
≥18 months109 (96)109 (96)
Age Category n (%)
Infant Toddler (Age <2)12 (11)18 (16)
Child (2 to 11 years)97 (86)94 (83)
Adolescent (12 to 17 years)4 (3)1 (1)
Race n (%)
White95 (84)90 (80)
Black or African American8 (7)8 (7)
Asian2 (2)4 (3)
Native Hawaiian or Other Pacific Islander02 (2)
Multiple1 (1)2 (2)
Other1 (1)0
Unknown6 (5)7 (6)
Ethnicity n (%)
Hispanic or Latino11 (10)11 (10)
Not Hispanic or Latino100 (88)96 (85)
Unknown2 (2)6 (5)
Country n (%)
Australia1 (1)3 (3)
Canada11 (10)13 (11)
United States101 (89)97 (86)

SD=standard deviation
Source: From Company Submission

Table 7. Baseline Demographics (Safety Population)

 UNITUXIN/RA
N=134
RA
N=106
Demographic Subgroup
Sex
Male80 (60)59 (56)
Female54 (40)47 (44)
Age at Enrollment (years)
N134106
Mean (SD)4.6 (3)4 (2)
Median43.6
Min, Max1.0, 15.31.0, 13.3
Dichotomized Age
<18 months3 (2)3 (3)
≥18 months131 (98)103 (97)
Age Category n (%)
Infant toddler (age <2)12 (9)17 (16)
Child (2 to 11 years)116 (87)88 (83)
Adolescent (12 to 17 years)6 (5)1 (1)
Race n (%)
White108 (81)84 (79)
Black or African American12 (9)7 (6.6)
Asian4 (3)4 (3.8)
Native Hawaiian or Other Pacific Islander02 (2)
American Indian or Alaska Native00
Multiple2 (2)2 (2)
Other1 (0.7)0
Unknown7 (5.2)7 (6.6)
Ethnicity n (%)
Hispanic or Latino15 (11)10 (9)
Not Hispanic or Latino117 (87)90 (85)
Unknown2 (1.5)6 (5.7)

Source: From Company Submission

How were the trials designed?

The trial randomly assigned half of the 226 patients enrolled to receive standard treatment (13-cis-retinoic acid, or RA) for 6 treatment cycles and the other half to receive UNITUXIN in combination with RA and GM-CSF (during Cycles 1, 3, and 5) and in combination with RA and IL-2 (during Cycles 2 and 4) followed by one cycle of RA alone.

The trial compared the amount of time from trial enrollment in the two treatment groups to either 1) growth of the neuroblastoma tumor or 2) patient death.

How were the trials designed?

The safety and effectiveness of Unituxin were evaluated in a randomized, open-label, multicenter trial conducted in pediatric patients with high-risk neuroblastoma. All patients had received prior therapy consisting of induction combination chemotherapy, maximum feasible surgical resection, myeloablative consolidation chemotherapy followed by autologous stem cell transplant, and radiation therapy to residual soft tissue disease. Patients were randomized between Day 50 and Day 77 post-autologous stem cell transplantation.

The major efficacy outcome measure was investigator-assessed event-free survival (EFS), defined as the time from randomization to the first occurrence of relapse, progressive disease, secondary malignancy, or death. Overall survival (OS) was also evaluated.  After observing a numerical improvement in EFS based on the seventh interim analysis, the Data Monitoring Committee recommended termination of accrual.

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

MEDICAL REVIEW

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