Trial Outcomes & Findings for A Pharmacokinetic (PK) Study of Nilotinib in Pediatric Patients With Philadelphia Chromosome-positive (Ph+) Chronic Myelogenous Leukemia (CML) or Acute Lymphoblastic Leukemia (ALL) (NCT NCT01077544)

NCT ID: NCT01077544

Last Updated: 2020-12-29

Results Overview

The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose on Cycle 1 Day 1.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

15 participants

Primary outcome timeframe

Cycle 1 Day 1

Results posted on

2020-12-29

Participant Flow

Participant milestones

Participant milestones
Measure
Group 1
1 year to \< 10 years pediatric patients
Group 2
\>= 10 years to \<18 years pediatric patients
Overall Study
STARTED
8
7
Overall Study
COMPLETED
5
2
Overall Study
NOT COMPLETED
3
5

Reasons for withdrawal

Reasons for withdrawal
Measure
Group 1
1 year to \< 10 years pediatric patients
Group 2
\>= 10 years to \<18 years pediatric patients
Overall Study
New Cancer Therapy
3
3
Overall Study
Adverse Event
0
1
Overall Study
Disease Progression
0
1

Baseline Characteristics

A Pharmacokinetic (PK) Study of Nilotinib in Pediatric Patients With Philadelphia Chromosome-positive (Ph+) Chronic Myelogenous Leukemia (CML) or Acute Lymphoblastic Leukemia (ALL)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure
Group 1
n=8 Participants
1 year to \< 10 years pediatric patients
Group 2
n=7 Participants
\>= 10 years to \<18 years pediatric patients
Total
n=15 Participants
Total of all reporting groups
Age, Continuous
6.8 Years
STANDARD_DEVIATION 1.16 • n=5 Participants
13.7 Years
STANDARD_DEVIATION 2.81 • n=7 Participants
10.0 Years
STANDARD_DEVIATION 4.12 • n=5 Participants
Sex: Female, Male
Female
3 Participants
n=5 Participants
4 Participants
n=7 Participants
7 Participants
n=5 Participants
Sex: Female, Male
Male
5 Participants
n=5 Participants
3 Participants
n=7 Participants
8 Participants
n=5 Participants
Weight
24.60 kg
STANDARD_DEVIATION 4.739 • n=5 Participants
48.89 kg
STANDARD_DEVIATION 17.533 • n=7 Participants
35.93 kg
STANDARD_DEVIATION 17.328 • n=5 Participants
Height
119.9 cm
STANDARD_DEVIATION 7.49 • n=5 Participants
158.0 cm
STANDARD_DEVIATION 16.32 • n=7 Participants
137.7 cm
STANDARD_DEVIATION 23.02 • n=5 Participants
Body Mass Index (BMI)
16.962 kg/m^2
STANDARD_DEVIATION 1.7654 • n=5 Participants
18.944 kg/m^2
STANDARD_DEVIATION 3.4563 • n=7 Participants
17.887 kg/m^2
STANDARD_DEVIATION 2.7795 • n=5 Participants

PRIMARY outcome

Timeframe: Cycle 1 Day 1

Population: Pharmacokinetic Analysis Set (PAS) consists of all patients who received the nilotinib dose on Day 1, had an evaluable Day 1 PK profile or provided at least one evaluable steady state trough concentration.

The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose on Cycle 1 Day 1.

Outcome measures

Outcome measures
Measure
Group 1
n=7 Participants
1 year to \< 10 years pediatric patients
Group 2
n=7 Participants
\>= 10 years to \<18 years pediatric patients
Summary of Nilotinib Non-compartmental PK Parameters: Cmax
405.111 ng/mL
Geometric Coefficient of Variation 42.5
402.715 ng/mL
Geometric Coefficient of Variation 35.2

PRIMARY outcome

Timeframe: Cycle 1 Day 1

Population: Pharmacokinetic Analysis Set (PAS) consists of all patients who received the nilotinib dose on Day 1, had an evaluable Day 1 PK profile or provided at least one evaluable steady state trough concentration.

The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose on Cycle 1 Day 1.

Outcome measures

Outcome measures
Measure
Group 1
n=7 Participants
1 year to \< 10 years pediatric patients
Group 2
n=7 Participants
\>= 10 years to \<18 years pediatric patients
Summary of Nilotinib Non-compartmental PK Parameters: Tmax
2.000 h
Full Range 163.1050 • Interval 1.02 to 7.08
3.000 h
Full Range 140.8314 • Interval 2.0 to 7.88

PRIMARY outcome

Timeframe: Cycle 1 Day 1

Population: Pharmacokinetic Analysis Set (PAS) consists of all patients who received the nilotinib dose on Day 1, had an evaluable Day 1 PK profile or provided at least one evaluable steady state trough concentration.

The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose on Cycle 1 Day 1.

Outcome measures

Outcome measures
Measure
Group 1
n=7 Participants
1 year to \< 10 years pediatric patients
Group 2
n=7 Participants
\>= 10 years to \<18 years pediatric patients
Summary of Nilotinib Non-compartmental PK Parameters: AUClast (Last = 24h)
4160.969 ng*h/mL
Geometric Coefficient of Variation 38.5
5707.368 ng*h/mL
Geometric Coefficient of Variation 51.2

PRIMARY outcome

Timeframe: Cycle 1 Day 1

Population: Pharmacokinetic Analysis Set (PAS) consists of all patients who received the nilotinib dose on Day 1, had an evaluable Day 1 PK profile or provided at least one evaluable steady state trough concentration.

The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose on Cycle 1 Day 1.

Outcome measures

Outcome measures
Measure
Group 1
n=7 Participants
1 year to \< 10 years pediatric patients
Group 2
n=7 Participants
\>= 10 years to \<18 years pediatric patients
Summary of Nilotinib Non-compartmental PK Parameters: AUC0-12h
2795.782 ng*h/mL
Geometric Coefficient of Variation 35.7
3393.296 ng*h/mL
Geometric Coefficient of Variation 30.4

PRIMARY outcome

Timeframe: Cycle 1 Day 8 - Cycle 1 Day 28

Population: Pharmacokinetic Analysis Set (PAS) consists of all patients who received the nilotinib dose on Day 1, had an evaluable Day 1 PK profile or provided at least one evaluable steady state trough concentration.

The steady-state PK profiles of nilotinib in pediatric patients were estimated using trough sampling following multiple 230 mg/m2 bid doses

Outcome measures

Outcome measures
Measure
Group 1
n=7 Participants
1 year to \< 10 years pediatric patients
Group 2
n=7 Participants
\>= 10 years to \<18 years pediatric patients
Summary of Nilotinib Steady-state PK Parameters: AUCss
15129.182 ng*h/mL
Geometric Coefficient of Variation 38.0
14383.076 ng*h/mL
Geometric Coefficient of Variation 33.6

PRIMARY outcome

Timeframe: Cycle 1 Day 8 - Cycle 1 day 28

Population: Pharmacokinetic Analysis Set (PAS) consists of all patients who received the nilotinib dose on Day 1, had an evaluable Day 1 PK profile or provided at least one evaluable steady state trough concentration.

The steady-state PK profiles of nilotinib in pediatric patients were estimated using trough sampling following multiple 230 mg/m2 bid doses

Outcome measures

Outcome measures
Measure
Group 1
n=7 Participants
1 year to \< 10 years pediatric patients
Group 2
n=7 Participants
\>= 10 years to \<18 years pediatric patients
Summary of Nilotinib Steady-state PK Parameters: CLF (Body Surface Area (BSA) Adjusted)
15.356 L/h/m^2)
Geometric Coefficient of Variation 38.7
15.922 L/h/m^2)
Geometric Coefficient of Variation 37.0

PRIMARY outcome

Timeframe: Cycle 1 Day 8 - Cycle 1 Day 28

Population: Pharmacokinetic Analysis Set (PAS) consists of all patients who received the nilotinib dose on Day 1, had an evaluable Day 1 PK profile or provided at least one evaluable steady state trough concentration.

The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose.

Outcome measures

Outcome measures
Measure
Group 1
n=7 Participants
1 year to \< 10 years pediatric patients
Group 2
n=7 Participants
\>= 10 years to \<18 years pediatric patients
Summary of Nilotinib Steady-state PK Parameters: Cmin
804.791 ng/mL
Geometric Coefficient of Variation 33.7
1072.850 ng/mL
Geometric Coefficient of Variation 20.5

SECONDARY outcome

Timeframe: minimum of 12 cycles (28 days per cycle)

Population: Full analysis set (FAS): consists of all patients who passed the screening and are enrolled into the study. Patients may or may not have taken study drug.

A confirmed complete hematological response (CHR) is defined when all of the following criteria are achieved at two consecutive assessments, at least 4 weeks apart: white blood cell (WBC) count \< 10 × 109/L; platelet \< 450 × 109/L; basophils \< 5%; no blasts and promyelocytes in peripheral blood (PB); myelocytes + metamyelocytes \< 5% in PB; and no extramedullary involvement. The information used for hematological assessment was to be obtained from the laboratory and extramedullary data, all merged by patient and date.

Outcome measures

Outcome measures
Measure
Group 1
n=5 Participants
1 year to \< 10 years pediatric patients
Group 2
n=6 Participants
\>= 10 years to \<18 years pediatric patients
Number of Ph+ CML Participants With Confirmed Complete Hematologic Response (CHR)
Yes
5 Participants
5 Participants
Number of Ph+ CML Participants With Confirmed Complete Hematologic Response (CHR)
No
0 Participants
1 Participants

SECONDARY outcome

Timeframe: minimum of 12 cycles (28 days per cycle)

Population: FAS consist of all patients (pts) who passed screening \& are enrolled into study. Patients may or may not have taken study drug. One (1) Ph+ CML patient in Group 2 was Ph+ at baseline \& discontinued study prior to subsequent cytogenetic assessment. This pt doesn't appear in any cytogenic response category.

Cytogenetic response was initially assessed as the percentage of Ph+ metaphases in the bone marrow (BM) and performed within 21 days prior to study entry. A major cytogenetic response (0% to 35% Ph+ metaphases test positive for the Philadelphia chromosome) combines both complete cytogenetic (CCyR) and partial cytogenetic response (PCyR). CCyR implies 0% Ph+ metaphases in the BM, PCyR is \> 0% to 35%, minor cytogenetic response (mCyR) is \> 35% to 65%, minimal response is \> 65% to 95% and no response is \> 95% Ph+ metaphases in the BM.

Outcome measures

Outcome measures
Measure
Group 1
n=5 Participants
1 year to \< 10 years pediatric patients
Group 2
n=6 Participants
\>= 10 years to \<18 years pediatric patients
Number of Ph+ CML Participants With Cytogenic Response
Complete cytogenic response (CCyR)
2 Participants
2 Participants
Number of Ph+ CML Participants With Cytogenic Response
Partial cytogenic response (PCyR)
0 Participants
1 Participants
Number of Ph+ CML Participants With Cytogenic Response
Minor cytogenic response (mCyR)
0 Participants
1 Participants
Number of Ph+ CML Participants With Cytogenic Response
Minimal
0 Participants
0 Participants
Number of Ph+ CML Participants With Cytogenic Response
None
0 Participants
0 Participants
Number of Ph+ CML Participants With Cytogenic Response
Absence of Ph+ at baseline
3 Participants
1 Participants

SECONDARY outcome

Timeframe: minimum of 12 cycles (28 days per cycle)

Population: Full analysis set (FAS): consists of all patients who passed the screening and are enrolled into the study. Patients may or may not have taken study drug.

The bcr-abl gene fusion encodes for a BCR-ABL fusion protein. Depending on the precise location of the fusion, the molecular weight of this protein can range from 185 to 210 kDa. Consequently BCR-ABL is referred to as p185 or p210 transcript. For the patients expressing the major BCR-ABL transcript p210, molecular response was defined and reported as the percent ratio of BCR-ABL transcripts/control gene transcripts converted to a reference standard according to the International Scale (IS). A major molecular response (MMR) is defined as a BCR-ABL/control gene ratio ≤ 0.1% (equal to a 3 log reduction in BCR-ABL transcripts) on the IS. In this study, the control gene was abl.

Outcome measures

Outcome measures
Measure
Group 1
n=5 Participants
1 year to \< 10 years pediatric patients
Group 2
n=6 Participants
\>= 10 years to \<18 years pediatric patients
Number of Ph+ CML Participants With Major Molecular Response (MMR)
Yes
1 Participants
2 Participants
Number of Ph+ CML Participants With Major Molecular Response (MMR)
No
4 Participants
4 Participants

SECONDARY outcome

Timeframe: minimum of 12 cycles (28 days per cycle)

Population: Full analysis set (FAS): consists of all patients who passed the screening and are enrolled into the study. Patients may or may not have taken study drug.

Best Response in Ph+ ALL patients was defined as either Complete Remission (CR) with platelet recovery, Complete Remission (CR) with incomplete platelet recovery, Partial Remission (PR) or Stable disease. Stable disease was defined is defined as failure to qualify for either CR, PR, or progressive disease.

Outcome measures

Outcome measures
Measure
Group 1
n=3 Participants
1 year to \< 10 years pediatric patients
Group 2
n=1 Participants
\>= 10 years to \<18 years pediatric patients
Efficacy Endpoints for Ph+ ALL Patients
Complete Remission with platelet recovery
2 Participants
1 Participants
Efficacy Endpoints for Ph+ ALL Patients
Complete Remission w/incomplete platelet recovery
0 Participants
0 Participants
Efficacy Endpoints for Ph+ ALL Patients
Partial remission
0 Participants
0 Participants
Efficacy Endpoints for Ph+ ALL Patients
Stable disease
1 Participants
0 Participants
Efficacy Endpoints for Ph+ ALL Patients
Progressive disease
0 Participants
0 Participants

Adverse Events

Group 1

Serious events: 2 serious events
Other events: 8 other events
Deaths: 0 deaths

Group 2

Serious events: 3 serious events
Other events: 7 other events
Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure
Group 1
n=8 participants at risk
1 year to \< 10 years pediatric patients
Group 2
n=7 participants at risk
\>= 10 years to \<18 years pediatric patients
Blood and lymphatic system disorders
Neutropenia
0.00%
0/8
28.6%
2/7
Gastrointestinal disorders
Appendix disorder
12.5%
1/8
0.00%
0/7
General disorders
Influenza like illness
12.5%
1/8
0.00%
0/7
General disorders
Pyrexia
12.5%
1/8
0.00%
0/7
Renal and urinary disorders
Renal failure
0.00%
0/8
14.3%
1/7

Other adverse events

Other adverse events
Measure
Group 1
n=8 participants at risk
1 year to \< 10 years pediatric patients
Group 2
n=7 participants at risk
\>= 10 years to \<18 years pediatric patients
Blood and lymphatic system disorders
Haemolytic anaemia
0.00%
0/8
14.3%
1/7
Blood and lymphatic system disorders
Leukopenia
0.00%
0/8
14.3%
1/7
Blood and lymphatic system disorders
Lymphopenia
0.00%
0/8
14.3%
1/7
Blood and lymphatic system disorders
Neutropenia
0.00%
0/8
14.3%
1/7
Blood and lymphatic system disorders
Thrombocytopenia
0.00%
0/8
14.3%
1/7
Ear and labyrinth disorders
Ear pain
0.00%
0/8
28.6%
2/7
Gastrointestinal disorders
Abdominal pain
12.5%
1/8
28.6%
2/7
Gastrointestinal disorders
Abdominal pain upper
12.5%
1/8
14.3%
1/7
Gastrointestinal disorders
Constipation
0.00%
0/8
14.3%
1/7
Gastrointestinal disorders
Diarrhoea
12.5%
1/8
42.9%
3/7
Gastrointestinal disorders
Nausea
0.00%
0/8
42.9%
3/7
Gastrointestinal disorders
Odynophagia
12.5%
1/8
0.00%
0/7
Gastrointestinal disorders
Toothache
0.00%
0/8
14.3%
1/7
Gastrointestinal disorders
Vomiting
37.5%
3/8
42.9%
3/7
General disorders
Asthenia
0.00%
0/8
14.3%
1/7
General disorders
Catheter site pain
12.5%
1/8
0.00%
0/7
General disorders
Fatigue
25.0%
2/8
0.00%
0/7
General disorders
Malaise
0.00%
0/8
14.3%
1/7
General disorders
Mucosal inflammation
0.00%
0/8
14.3%
1/7
General disorders
Pyrexia
12.5%
1/8
14.3%
1/7
General disorders
Xerosis
12.5%
1/8
0.00%
0/7
Hepatobiliary disorders
Hyperbilirubinaemia
25.0%
2/8
28.6%
2/7
Infections and infestations
Bronchitis
0.00%
0/8
14.3%
1/7
Infections and infestations
Device related infection
12.5%
1/8
0.00%
0/7
Infections and infestations
Ear infection
12.5%
1/8
0.00%
0/7
Infections and infestations
Folliculitis
0.00%
0/8
28.6%
2/7
Infections and infestations
Fungal skin infection
0.00%
0/8
14.3%
1/7
Infections and infestations
Hand-foot-and-mouth disease
12.5%
1/8
0.00%
0/7
Infections and infestations
Lip infection
0.00%
0/8
14.3%
1/7
Infections and infestations
Nasopharyngitis
50.0%
4/8
0.00%
0/7
Infections and infestations
Oral candidiasis
0.00%
0/8
14.3%
1/7
Infections and infestations
Otitis media
12.5%
1/8
0.00%
0/7
Infections and infestations
Rhinitis
37.5%
3/8
14.3%
1/7
Infections and infestations
Skin infection
0.00%
0/8
28.6%
2/7
Infections and infestations
Tinea pedis
0.00%
0/8
14.3%
1/7
Infections and infestations
Tonsillitis
0.00%
0/8
14.3%
1/7
Infections and infestations
Upper respiratory tract infection
12.5%
1/8
14.3%
1/7
Investigations
Alanine aminotransferase increased
37.5%
3/8
14.3%
1/7
Investigations
Aspartate aminotransferase increased
37.5%
3/8
0.00%
0/7
Investigations
Bilirubin conjugated increased
12.5%
1/8
14.3%
1/7
Investigations
Blood bilirubin increased
25.0%
2/8
42.9%
3/7
Investigations
Blood bilirubin unconjugated increased
0.00%
0/8
14.3%
1/7
Investigations
Blood creatinine increased
0.00%
0/8
28.6%
2/7
Investigations
Blood phosphorus decreased
12.5%
1/8
0.00%
0/7
Investigations
Blood sodium decreased
12.5%
1/8
0.00%
0/7
Investigations
Blood urea increased
0.00%
0/8
28.6%
2/7
Investigations
Blood uric acid increased
0.00%
0/8
28.6%
2/7
Investigations
Electrocardiogram QT prolonged
12.5%
1/8
0.00%
0/7
Investigations
Haematocrit decreased
0.00%
0/8
14.3%
1/7
Investigations
Haemoglobin decreased
0.00%
0/8
14.3%
1/7
Investigations
Neutrophil count increased
0.00%
0/8
14.3%
1/7
Investigations
Platelet count decreased
0.00%
0/8
14.3%
1/7
Investigations
Red blood cell count decreased
0.00%
0/8
14.3%
1/7
Investigations
Weight decreased
12.5%
1/8
0.00%
0/7
Investigations
White blood cell count decreased
0.00%
0/8
14.3%
1/7
Investigations
White blood cell count increased
0.00%
0/8
14.3%
1/7
Metabolism and nutrition disorders
Hypoalbuminaemia
12.5%
1/8
0.00%
0/7
Musculoskeletal and connective tissue disorders
Arthralgia
0.00%
0/8
42.9%
3/7
Musculoskeletal and connective tissue disorders
Back pain
12.5%
1/8
0.00%
0/7
Musculoskeletal and connective tissue disorders
Bone pain
12.5%
1/8
14.3%
1/7
Musculoskeletal and connective tissue disorders
Muscle spasms
12.5%
1/8
0.00%
0/7
Musculoskeletal and connective tissue disorders
Musculoskeletal pain
12.5%
1/8
0.00%
0/7
Musculoskeletal and connective tissue disorders
Neck pain
12.5%
1/8
14.3%
1/7
Musculoskeletal and connective tissue disorders
Pain in extremity
37.5%
3/8
14.3%
1/7
Musculoskeletal and connective tissue disorders
Tendon pain
0.00%
0/8
14.3%
1/7
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma
25.0%
2/8
0.00%
0/7
Nervous system disorders
Headache
50.0%
4/8
28.6%
2/7
Nervous system disorders
Paraesthesia
0.00%
0/8
14.3%
1/7
Nervous system disorders
Peripheral sensory neuropathy
12.5%
1/8
0.00%
0/7
Nervous system disorders
Presyncope
0.00%
0/8
14.3%
1/7
Nervous system disorders
Syncope
0.00%
0/8
14.3%
1/7
Reproductive system and breast disorders
Vulvovaginal pruritus
12.5%
1/8
0.00%
0/7
Respiratory, thoracic and mediastinal disorders
Cough
25.0%
2/8
28.6%
2/7
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
0.00%
0/8
14.3%
1/7
Respiratory, thoracic and mediastinal disorders
Pharyngeal erythema
12.5%
1/8
0.00%
0/7
Respiratory, thoracic and mediastinal disorders
Productive cough
0.00%
0/8
14.3%
1/7
Skin and subcutaneous tissue disorders
Dermatitis atopic
12.5%
1/8
0.00%
0/7
Skin and subcutaneous tissue disorders
Dry skin
0.00%
0/8
28.6%
2/7
Skin and subcutaneous tissue disorders
Dyshidrotic eczema
0.00%
0/8
14.3%
1/7
Skin and subcutaneous tissue disorders
Eczema
25.0%
2/8
14.3%
1/7
Skin and subcutaneous tissue disorders
Exfoliative rash
12.5%
1/8
0.00%
0/7
Skin and subcutaneous tissue disorders
Psoriasis
12.5%
1/8
0.00%
0/7
Skin and subcutaneous tissue disorders
Rash
37.5%
3/8
28.6%
2/7
Skin and subcutaneous tissue disorders
Rash erythematous
12.5%
1/8
0.00%
0/7
Skin and subcutaneous tissue disorders
Rash maculo-papular
12.5%
1/8
0.00%
0/7
Skin and subcutaneous tissue disorders
Rash papular
12.5%
1/8
0.00%
0/7
Skin and subcutaneous tissue disorders
Skin lesion
0.00%
0/8
14.3%
1/7

Additional Information

Study Director

Novartis Pharmaceuticals

Phone: 82-778-8300

Results disclosure agreements

  • Principal investigator is a sponsor employee The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of pooled data (i.e.,data from all sites) in clinical trial or disclosure of trial results in their entirety.
  • Publication restrictions are in place

Restriction type: OTHER