Acute Lymphoblastic Leukemia, Chronic Myeloid Leukemia
Conditions
Keywords
Chronic Myeloid Leukemia, Acute Lymphoblastic Leukemia, Ph+ CML, Ph+ ALL, pediatric, nilotinib, imatinib, chronic phase, accelerated phase, newly diagnosed Ph+ CML, dasatinib
Brief summary
This study will assess the pharmacokinetics of nilotinib in Ph+ CML pediatric patients that are newly diagnosed or resistant or intolerant to imatinib or dasatinib or refractory or relapsed Ph+ ALL compared to the adult populations. It will also evaluate safety and activity of nilotinib as secondary objectives.
Interventions
DRUGNilotinib
Nilotinib capsules were delivered in bottles with dose strengths of 50mg, 150mg and 200mg. Patients were administered nilotinib 230 mg/m2 (per BSA) bid, orally, rounded to the nearest 50 mg (max single dose 400 mg) for 28 days (1 cycle) for up to 12 cycles prior to protocol amendment 3 and up to 24 cycles post amendment 3. Capsules were to be swallowed whole with water. Apple sauce (puréed apple) may have been used as a vehicle for dosing where capsules were not able to be swallowed whole with water.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Must have one of the following: newly diagnosed CP Ph+CML, CP or AP resistant/ intolerant to imatinib and/or dasatinib, or Ph+ ALL either relapsed after or refractory to standard therapy * adequate renal, hepatic and pancreatic function
Exclusion criteria
* patients receiving therapy with strong CYP3A4 inhibitors and/or inducers and treatments cannot be stopped or changed to a different medication at least 14 days prior to starting study drug * patients receiving therapy with any medications with a known risk or possible risk to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. * gastrointestinal impairment or disease that may interfere with drug absorption * liver, pancreatic or severe renal disease unrelated to disease under study * impaired cardiac function * patients who received dasatinib within 3 days of starting study drug * patients who received imatinib within 5 days of starting study drug * patients receiving hydroxyurea or corticosteroids that has not been discontinued at least 1 week after initiation of nilotinib * patients who received hematopoietic growth factors within 7 days of starting study drug or Pegfilgrastim (Neulasta®) within 14 days of starting study drug * patients with Stem Cell Transplant (SCT) or Rescue without TBI: Evidence of active graft vs. host disease and \< 3 months since SCT Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Summary of Nilotinib Steady-state PK Parameters: Cmin | Cycle 1 Day 8 - Cycle 1 Day 28 | The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose. |
| Summary of Nilotinib Non-compartmental PK Parameters: AUClast (Last = 24h) | Cycle 1 Day 1 | 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. |
| Summary of Nilotinib Non-compartmental PK Parameters: AUC0-12h | Cycle 1 Day 1 | 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. |
| Summary of Nilotinib Steady-state PK Parameters: AUCss | Cycle 1 Day 8 - Cycle 1 Day 28 | The steady-state PK profiles of nilotinib in pediatric patients were estimated using trough sampling following multiple 230 mg/m2 bid doses |
| Summary of Nilotinib Steady-state PK Parameters: CLF (Body Surface Area (BSA) Adjusted) | Cycle 1 Day 8 - Cycle 1 day 28 | The steady-state PK profiles of nilotinib in pediatric patients were estimated using trough sampling following multiple 230 mg/m2 bid doses |
| Summary of Nilotinib Non-compartmental PK Parameters: Cmax | Cycle 1 Day 1 | 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. |
| Summary of Nilotinib Non-compartmental PK Parameters: Tmax | Cycle 1 Day 1 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Ph+ CML Participants With Cytogenic Response | minimum of 12 cycles (28 days per cycle) | 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. |
| Number of Ph+ CML Participants With Major Molecular Response (MMR) | minimum of 12 cycles (28 days per cycle) | 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. |
| Efficacy Endpoints for Ph+ ALL Patients | minimum of 12 cycles (28 days per cycle) | 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. |
| Number of Ph+ CML Participants With Confirmed Complete Hematologic Response (CHR) | minimum of 12 cycles (28 days per cycle) | 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. |
Countries
France, Italy, Netherlands, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Group 1 1 year to \< 10 years pediatric patients | 8 |
| Group 2 \>= 10 years to \<18 years pediatric patients | 7 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Disease Progression | 0 | 1 |
| Overall Study | New Cancer Therapy | 3 | 3 |
Baseline characteristics
| Characteristic | Group 1 | Group 2 | Total |
|---|---|---|---|
| Age, Continuous | 6.8 Years STANDARD_DEVIATION 1.16 | 13.7 Years STANDARD_DEVIATION 2.81 | 10.0 Years STANDARD_DEVIATION 4.12 |
| Body Mass Index (BMI) | 16.962 kg/m^2 STANDARD_DEVIATION 1.7654 | 18.944 kg/m^2 STANDARD_DEVIATION 3.4563 | 17.887 kg/m^2 STANDARD_DEVIATION 2.7795 |
| Height | 119.9 cm STANDARD_DEVIATION 7.49 | 158.0 cm STANDARD_DEVIATION 16.32 | 137.7 cm STANDARD_DEVIATION 23.02 |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Male | 5 Participants | 3 Participants | 8 Participants |
| Weight | 24.60 kg STANDARD_DEVIATION 4.739 | 48.89 kg STANDARD_DEVIATION 17.533 | 35.93 kg STANDARD_DEVIATION 17.328 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 8 | 7 / 7 |
| serious Total, serious adverse events | 2 / 8 | 3 / 7 |
Outcome results
Primary
Summary of Nilotinib Non-compartmental PK Parameters: AUC0-12h
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.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1 | Summary of Nilotinib Non-compartmental PK Parameters: AUC0-12h | 2795.782 ng*h/mL | Geometric Coefficient of Variation 35.7 |
| Group 2 | Summary of Nilotinib Non-compartmental PK Parameters: AUC0-12h | 3393.296 ng*h/mL | Geometric Coefficient of Variation 30.4 |
Primary
Summary of Nilotinib Non-compartmental PK Parameters: AUClast (Last = 24h)
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.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1 | Summary of Nilotinib Non-compartmental PK Parameters: AUClast (Last = 24h) | 4160.969 ng*h/mL | Geometric Coefficient of Variation 38.5 |
| Group 2 | Summary of Nilotinib Non-compartmental PK Parameters: AUClast (Last = 24h) | 5707.368 ng*h/mL | Geometric Coefficient of Variation 51.2 |
Primary
Summary of Nilotinib Non-compartmental PK Parameters: Cmax
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.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1 | Summary of Nilotinib Non-compartmental PK Parameters: Cmax | 405.111 ng/mL | Geometric Coefficient of Variation 42.5 |
| Group 2 | Summary of Nilotinib Non-compartmental PK Parameters: Cmax | 402.715 ng/mL | Geometric Coefficient of Variation 35.2 |
Primary
Summary of Nilotinib Non-compartmental PK Parameters: Tmax
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Group 1 | Summary of Nilotinib Non-compartmental PK Parameters: Tmax | 2.000 h | Full Range 163.105 |
| Group 2 | Summary of Nilotinib Non-compartmental PK Parameters: Tmax | 3.000 h | Full Range 140.8314 |
Primary
Summary of Nilotinib Steady-state PK Parameters: AUCss
The steady-state PK profiles of nilotinib in pediatric patients were estimated using trough sampling following multiple 230 mg/m2 bid doses
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1 | Summary of Nilotinib Steady-state PK Parameters: AUCss | 15129.182 ng*h/mL | Geometric Coefficient of Variation 38 |
| Group 2 | Summary of Nilotinib Steady-state PK Parameters: AUCss | 14383.076 ng*h/mL | Geometric Coefficient of Variation 33.6 |
Primary
Summary of Nilotinib Steady-state PK Parameters: CLF (Body Surface Area (BSA) Adjusted)
The steady-state PK profiles of nilotinib in pediatric patients were estimated using trough sampling following multiple 230 mg/m2 bid doses
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1 | 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 |
| Group 2 | Summary of Nilotinib Steady-state PK Parameters: CLF (Body Surface Area (BSA) Adjusted) | 15.922 L/h/m^2) | Geometric Coefficient of Variation 37 |
Primary
Summary of Nilotinib Steady-state PK Parameters: Cmin
The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Group 1 | Summary of Nilotinib Steady-state PK Parameters: Cmin | 804.791 ng/mL | Geometric Coefficient of Variation 33.7 |
| Group 2 | Summary of Nilotinib Steady-state PK Parameters: Cmin | 1072.850 ng/mL | Geometric Coefficient of Variation 20.5 |
Secondary
Efficacy Endpoints for Ph+ ALL Patients
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1 | Efficacy Endpoints for Ph+ ALL Patients | Complete Remission w/incomplete platelet recovery | 0 Participants |
| Group 1 | Efficacy Endpoints for Ph+ ALL Patients | Stable disease | 1 Participants |
| Group 1 | Efficacy Endpoints for Ph+ ALL Patients | Partial remission | 0 Participants |
| Group 1 | Efficacy Endpoints for Ph+ ALL Patients | Progressive disease | 0 Participants |
| Group 1 | Efficacy Endpoints for Ph+ ALL Patients | Complete Remission with platelet recovery | 2 Participants |
| Group 2 | Efficacy Endpoints for Ph+ ALL Patients | Progressive disease | 0 Participants |
| Group 2 | Efficacy Endpoints for Ph+ ALL Patients | Complete Remission with platelet recovery | 1 Participants |
| Group 2 | Efficacy Endpoints for Ph+ ALL Patients | Complete Remission w/incomplete platelet recovery | 0 Participants |
| Group 2 | Efficacy Endpoints for Ph+ ALL Patients | Partial remission | 0 Participants |
| Group 2 | Efficacy Endpoints for Ph+ ALL Patients | Stable disease | 0 Participants |
Secondary
Number of Ph+ CML Participants With Confirmed Complete Hematologic Response (CHR)
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1 | Number of Ph+ CML Participants With Confirmed Complete Hematologic Response (CHR) | Yes | 5 Participants |
| Group 1 | Number of Ph+ CML Participants With Confirmed Complete Hematologic Response (CHR) | No | 0 Participants |
| Group 2 | Number of Ph+ CML Participants With Confirmed Complete Hematologic Response (CHR) | Yes | 5 Participants |
| Group 2 | Number of Ph+ CML Participants With Confirmed Complete Hematologic Response (CHR) | No | 1 Participants |
Secondary
Number of Ph+ CML Participants With Cytogenic Response
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1 | Number of Ph+ CML Participants With Cytogenic Response | Complete cytogenic response (CCyR) | 2 Participants |
| Group 1 | Number of Ph+ CML Participants With Cytogenic Response | Partial cytogenic response (PCyR) | 0 Participants |
| Group 1 | Number of Ph+ CML Participants With Cytogenic Response | Minor cytogenic response (mCyR) | 0 Participants |
| Group 1 | Number of Ph+ CML Participants With Cytogenic Response | Minimal | 0 Participants |
| Group 1 | Number of Ph+ CML Participants With Cytogenic Response | None | 0 Participants |
| Group 1 | Number of Ph+ CML Participants With Cytogenic Response | Absence of Ph+ at baseline | 3 Participants |
| Group 2 | Number of Ph+ CML Participants With Cytogenic Response | None | 0 Participants |
| Group 2 | Number of Ph+ CML Participants With Cytogenic Response | Complete cytogenic response (CCyR) | 2 Participants |
| Group 2 | Number of Ph+ CML Participants With Cytogenic Response | Minimal | 0 Participants |
| Group 2 | Number of Ph+ CML Participants With Cytogenic Response | Partial cytogenic response (PCyR) | 1 Participants |
| Group 2 | Number of Ph+ CML Participants With Cytogenic Response | Absence of Ph+ at baseline | 1 Participants |
| Group 2 | Number of Ph+ CML Participants With Cytogenic Response | Minor cytogenic response (mCyR) | 1 Participants |
Secondary
Number of Ph+ CML Participants With Major Molecular Response (MMR)
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group 1 | Number of Ph+ CML Participants With Major Molecular Response (MMR) | Yes | 1 Participants |
| Group 1 | Number of Ph+ CML Participants With Major Molecular Response (MMR) | No | 4 Participants |
| Group 2 | Number of Ph+ CML Participants With Major Molecular Response (MMR) | Yes | 2 Participants |
| Group 2 | Number of Ph+ CML Participants With Major Molecular Response (MMR) | No | 4 Participants |