A Multi-center, Open Label, Non-controlled Phase II Study to Evaluate Efficacy and Safety of Oral Nilotinib in Pediatric Patients With Newly Diagnosed Ph+ Chronic Myelogenous Leukemia (CML) in Chronic Phase (CP) or With Ph+ CML in CP or Accelerated Phase (AP) Resistant or Intolerant to Either Imatinib or Dasatinib
Overview
- Phase
- Phase 2
- Intervention
- nilotinib
- Conditions
- Philadelphia Positive (Ph+) Chronic Myelogenous Leukemia
- Sponsor
- Novartis Pharmaceuticals
- Enrollment
- 59
- Locations
- 11
- Primary Endpoint
- MMR Rate by 12 Cycles in Newly Diagnosed Ph+ CML-CP Patients
- Status
- Completed
- Last Updated
- 5 years ago
Overview
Brief Summary
To evaluate the safety, efficacy and pharmacokinetics of nilotinib over time in the Ph+ chronic myelogenous leukemia (CML) in pediatric patients (from 1 to <18 years).
Detailed Description
The study was designed as a multi-center, open-label, non-controlled phase II study to assess efficacy, safety and PK parameters of 230 mg/m2 twice daily nilotinib in pediatric patients (1 to \<18 years old). The study population consisted of three cohorts of Ph+ CML pediatric patients: * Cohort 1: Ph+ CML-CP patients resistant or intolerant to either imatinib or dasatinib * Cohort 2: Ph+ CML-AP patients resistant or intolerant to either imatinib or dasatinib * Cohort 3: Newly-diagnosed Ph+ CML-CP patients in first chronic phase A minimum number of 50 pediatric patients (from 1 to \<18 years) were enrolled in the study. Of them, at least 15 patients were Ph+ CML-CP patients resistant or intolerant to either imatinib or dasatinib, and at least 15 were newly-diagnosed Ph+ CML-CP patients in first chronic phase patients. There was no minimum number of patients required for Ph+ CML-AP patients resistant or intolerant to either imatinib or dasatinib. Based on enrollment forecasts as of Jan 2015, and to reflect the agreements with the US FDA and the PDCO, the study remained open for enrollment until the targeted number of 50 patients with at least 15 newly diagnosed Ph+CML patients was achieved or until 31May2015, whichever was later. Patients who completed the study were treated with nilotinib for a total of 66 cycles of 28 days unless the patient prematurely discontinued study treatment. The primary analysis cut-off date was the date when all patients enrolled in the trial either completed their visit for treatment cycle 12 or had discontinued study treatment early (EoT/early discontinuation visit). These analyses were reported in the 12-cycle clinical study report (CSR). A 24-cycle analysis was done when all patients had either completed their 24-cycle treatment visit or had discontinued study treatment early. At trial end, a final comprehensive CSR of all data collected during the trial was produced.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Newly diagnosed and untreated Ph+ CML CP or Ph+ CML CP or AP resistant or intolerant to either imatinib or dasatinib
- •Karnofsky ≥ 50% for patients \> 10 years of age and Lansky ≥ 50 for patients ≤ 10 years of age
- •Adequate renal, hepatic and pancreatic function
- •Potassium, magnesium, phosphorus and total calcium values ≥ LLN (lower limit of normal)
- •Written informed consent
Exclusion Criteria
- •Treatment with strong CYP3A4 inhibitors or inducers
- •Use or planned use of any medications that have a known risk or possible risk to prolong the QT interval
- •Acute or chronic liver, pancreatic or severe renal disease
- •History of pancreatitis or chronic pancreatitis.
- •Impaired cardiac function
- •No evidence of active graft vs host and \<3mo since Stem Cell Transplant
- •Total body irradiation (TBI) or craniospinal radiation therapy \<6months
- •Hypersensitivity to the active ingredient or any of the excipients including lactose.
- •the criteria regarding pregnancy and contraception
- •Active or systemic bacterial, fungal, or viral infection
Arms & Interventions
Newly diagnosed and untreated Ph+ CML in first CP
Diagnosis within 6 months of date of first cytogenetic analysis confirming Philadelphia chromosome with (9;22) translocation by standard conventional cytogenetic analysis.
Intervention: nilotinib
Resistant/intolerant Ph+ CML in CP
Resistant or Intolerant to either imatinib or dasatinib
Intervention: nilotinib
Resistant/intolerant Ph+ CML in AP
Resistant or intolerant to either imatinib or dasatinib - at the end no patients were enrolled in this arm.
Intervention: nilotinib
Outcomes
Primary Outcomes
MMR Rate by 12 Cycles in Newly Diagnosed Ph+ CML-CP Patients
Time Frame: 12 cycles
MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. A patient was counted as having MMR by 12 cycles if the patient met the MMR criteria at least once at any time between first study drug intake and Cycle 12 visit included.
Rate of Major Molecular Response (MMR) at 6 Cycles for Ph+ CML CP Patients Resistant or Intolerant to Imatinib or Dasatinib
Time Frame: 6 cycles
MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. A patient was counted as having MMR at 6 cycles if the patient met the MMR criteria at the Cycle 6 Visit.
Rate of Complete Cytogenic Response (CCyR) at 12 Cycles in Newly Diagnosed Ph+ CML-CP Patients
Time Frame: 12 cycles
Cytogenetic response is assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow. Complete Cytogenetic Response (CCyR) is defined as 0% of Ph+ metaphases. A patient was counted as CCyR at 12 cycles if the patient met the CCyR criteria at the Cycle 12 Visit.
Secondary Outcomes
- MMR Rate by Time Points in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib(By 3, 6, 9 , 12, 24, 36, 48, 66 cycles ( 1 cycle = 28 days))
- Best BCR-ABL Ratio Categories for Newly Diagnosed Ph+ CML-CP - Overall(up to 66 cycles (1 cycle = 28 days))
- Time to First MMR Among Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients Who Achieved MMR(From first dosing to the first MMR within 66 cycles period)
- Time to First MMR Among Newly Diagnosed Ph+ CML-CP Patients Who Achieved MMR(From first dosing to the first MMR within 66 cycles period)
- Best BCR-ABL Ratio Categories for Resistant/Intolerant Ph+ CML - Overall(up to 66 cycles (1 cycle = 28 days))
- Duration of First MMR Among Newly Diagnosed Patients Who Achieved MMR(from MMR until confirmed loss of MMR (Assessed up to 66 cycles)es))
- Best Complete Hematological Response (CHR) by Time Point(cycle 3, 6, 9, 12, 18, 24, 36, 48, 66)
- Overall Survival (OS) in Newly Diagnosed CML-CP Patients(from first dosing to death up to 66 cycles)
- MMR Rate by Time Points in Newly Diagnosed Ph+ CML-CP Patients(by 3, 6, 9, 12, 24, 36, 48, 66 cycles (1 cycle = 28 days))
- Kaplan-Meier Estimates of Duration of First Complete Cytogenic Response (CCyR) Among Patients Who Achieved CCyR in Newly Diagnosed Ph+ CML-CP Patients(From CCyR to loss of CCyR up to 66 cycles)
- Event Free Survival in Newly Diagnosed CML-CP Patients(From first dosing to the disease progression or death up to 66 cycles)
- Pharmacokinetics: Steady State Concentration of Nilotinib in Newly Diagnosed CML-CP Patients(Cycle 1 Day 8)
- Best Complete Cytogenetic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients - Overall(up to 66 cycles)
- Duration of First MMR Among Patients Who Were Resistant or Intolerant to Either Imatinib or Dasatinib Who Achieved MMR(from MMR until confirmed loss of MMR (Assessed up to 66 cycles))
- Best Complete Cytogenetic Response (CCyR) Categories in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib - Overall(up to 66 cycles)
- Kaplan-Meier Estimates of Time to First Complete Cytogenic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients(From first dosing to the first CCyR up to 66 cycles)
- Kaplan-Meier Estimates of Time to First Major Cytogenetic Response (MCyR) in Newly Diagnosed CML-CP Patients(up to 66 cycles)
- Summary of Time to First Complete Hematological Response (CHR) Among Patients Who Achieved Confirmed CHR in Newly Diagnosed CML-CP Patients(from first dosing to CHR, UP TO 66 CYCLES)
- Overall Survival (OS) in Imatinib/Dasatinib Resistant/Intolerant CML-CP - Kaplan-Meier Estimates(from first dosing to death up to 66 cycles)
- Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle(By 3, 6, 9, 12, 18, 24, 36, 48, 66 cycles)
- Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation(up to Cycle 12)
- Summary of Time to First Complete Cytogenic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients(From first dosing to the first CCyR up to 66 cycles)
- Summary of Time to First Major Cytogenetic Response (MCyR) Among Patients Who Achieved MCyR in Newly Diagnosed CML-CP Patients(up to 66 cycles)
- Best Major Cytogenetic Response (MCyR) Rate by Time Point in Newly Diagnosed Ph+ CML Patients(6, 12, 18, 24, 36, 48, 66 cycles)
- Kaplan-Meier Estimates of Time to First Complete Hematological Response (CHR) in Newly Diagnosed CML-CP Patients(from first dosing to CHR, UP TO 66 CYCLES)
- Time to Disease Progression for Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients - Kaplan-Meier Estimates(From first dosing to the disease progression within 66 cycles)
- Event Free Survival in Imatinib/Dasatinib Resistant/Intolerant CML-CP Patients(From first dosing to the disease progression or death up to 66 cycles)
- Pharmacokinetics (PK): Steady State Concentration of Nilotinib in Imatinib/Dasatinib Resistant/Intolerant CML-CP Patients(Cycle 1 Day 8)
- Growth Data: Abnormal Height Standard Deviation Scores (SDS) Changes by Cohort(from first dosing to 66 cycles)
- Mutational Assessment of BCR-ABL(up to 66 cycles)