Clinical Trial: NCT01844765 - My Cancer Genome

NCT01844765

Description:

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).

Related Conditions:

Chronic Myeloid Leukemia

Recruiting Status:

Completed

Phase:

Phase 2

URL:

https://clinicaltrials.gov/show/NCT01844765

Trial Eligibility

Document

Title

Brief Title: Open Label, Phase II Study to Evaluate Efficacy and Safety of Oral Nilotinib in Philadelphia Positive (Ph+) Chronic Myelogenous Leukemia (CML) Pediatric Patients.
Official Title: 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

Clinical Trial IDs

ORG STUDY ID: CAMN107A2203
SECONDARY ID: 2013-000200-41
NCT ID: NCT01844765

Conditions

Philadelphia Positive (Ph+) Chronic Myelogenous Leukemia

Interventions

Drug	Synonyms	Arms
nilotinib	AMN107	Newly diagnosed and untreated Ph+ CML in first CP

Purpose

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.

Trial Arms

Name	Type	Description	Interventions
Newly diagnosed and untreated Ph+ CML in first CP	Experimental	Diagnosis within 6 months of date of first cytogenetic analysis confirming Philadelphia chromosome with (9;22) translocation by standard conventional cytogenetic analysis.	nilotinib
Resistant/intolerant Ph+ CML in CP	Experimental	Resistant or Intolerant to either imatinib or dasatinib	nilotinib
Resistant/intolerant Ph+ CML in AP	Experimental	Resistant or intolerant to either imatinib or dasatinib - at the end no patients were enrolled in this arm.	nilotinib

Eligibility Criteria

        Key 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

        Key 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

          -  known Hepatitis B, Hepatitis C, or HIV infection

Maximum Eligible Age:	17 Years
Minimum Eligible Age:	1 Year
Eligible Gender:	All
Healthy Volunteers:	No

Primary Outcome Measures

Measure:	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
Safety Issue:
Description:	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.

Secondary Outcome Measures

Measure:	MMR Rate by Time Points in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib
Time Frame:	By 3, 6, 9 , 12, 24, 36, 48, 66 cycles ( 1 cycle = 28 days)
Safety Issue:
Description:	Major molecular response (MMR) was defined as BCR-ABL/ABL % ≤ 0.1% by IS as measured by RQ-PCR, confirmed by duplicate analysis of the same sample.

Measure:	MMR Rate by Time Points in Newly Diagnosed Ph+ CML-CP Patients
Time Frame:	by 3, 6, 9, 12, 24, 36, 48, 66 cycles (1 cycle = 28 days)
Safety Issue:
Description:	Major molecular response (MMR) was defined as BCR-ABL/ABL % ≤ 0.1% by IS as measured by RQ-PCR, confirmed by duplicate analysis of the same sample.

Measure:	Best BCR-ABL Ratio Categories for Resistant/Intolerant Ph+ CML - Overall
Time Frame:	up to 66 cycles (1 cycle = 28 days)
Safety Issue:
Description:	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. BCR-ABL ratio by percentage: > 0.0032 to ≤ 0.01% is equal to a log reduction category of >= 4 to <4.5 -log reduction (MR4); BCR-ABL ratio by percentage: <=0.0032% is equal to a log reduction category of >= 4.5-log reduction (MMR4.5)

Measure:	Best BCR-ABL Ratio Categories for Newly Diagnosed Ph+ CML-CP - Overall
Time Frame:	up to 66 cycles (1 cycle = 28 days)
Safety Issue:
Description:	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. BCR-ABL ratio by percentage: > 0.0032 to ≤ 0.01% is equal to a log reduction category of >= 4 to <4.5 -log reduction (MR4); BCR-ABL ratio by percentage: <=0.0032% is equal to a log reduction category of >= 4.5-log reduction (MMR4.5)

Measure:	Time to First MMR Among Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients Who Achieved MMR
Time Frame:	From first dosing to the first MMR within 66 cycles period
Safety Issue:
Description:	Time from first study drug intake to first MMR amongst imatinib or dasatinib resistant or intolerant patients with CML-CP computed only for patients who achieved MMR.

Measure:	Time to First MMR Among Newly Diagnosed Ph+ CML-CP Patients Who Achieved MMR
Time Frame:	From first dosing to the first MMR within 66 cycles period
Safety Issue:
Description:	Time to MMR is the time from first study drug intake to first major molecular response computed only for participants who achieved MMR.

Measure:	Duration of First MMR Among Patients Who Were Resistant or Intolerant to Either Imatinib or Dasatinib Who Achieved MMR
Time Frame:	from MMR until confirmed loss of MMR (Assessed up to 66 cycles)
Safety Issue:
Description:	Duration of MMR is defined as the time between the date of the first MMR and the date of confirmed loss of MMR (i.e. the earliest of confirmed loss of MMR, CML-related death or progression to AP or BC). Participants without loss of MMR were censored at the last molecular assessment date.

Measure:	Duration of First MMR Among Newly Diagnosed Patients Who Achieved MMR
Time Frame:	from MMR until confirmed loss of MMR (Assessed up to 66 cycles)es)
Safety Issue:
Description:	Duration of MMR is defined as the time between the date of the first MMR and the date of confirmed loss of MMR (i.e. the earliest of confirmed loss of MMR, CML-related death or progression to AP or BC). Participants without loss of MMR were censored at the last molecular assessment date.

Measure:	Best Complete Cytogenetic Response (CCyR) Categories in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib - Overall
Time Frame:	up to 66 cycles
Safety Issue:
Description:	Complete cytogenetic response (CCyR) - 0% Ph+ metaphases Partial cytogenetic response (PCyR) - >0 to 35% Ph+ metaphases Minor cytogenetic response (mCyR) - >35 to 65% Ph+ metaphases Minimal - >65 to 95% Ph+ metaphases None - >95 to 100% Ph+ metaphases Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.

Measure:	Best Complete Cytogenetic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients - Overall
Time Frame:	up to 66 cycles
Safety Issue:
Description:	Complete cytogenetic response (CCyR) - 0% Ph+ metaphases No response - >95 to 100% Ph+ metaphases

Measure:	Summary of Time to First Complete Cytogenic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients
Time Frame:	From first dosing to the first CCyR up to 66 cycles
Safety Issue:
Description:	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 having CCyR by 6 cycles (respectively 12 cycles) if the patient met the CCyR criteria at least once at any time between first study drug intake and cycle 6 (cycle 12 respectively) visit included.

Measure:	Kaplan-Meier Estimates of Time to First Complete Cytogenic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients
Time Frame:	From first dosing to the first CCyR up to 66 cycles
Safety Issue:
Description:	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 having CCyR by 6 cycles (respectively 12 cycles) if the patient met the CCyR criteria at least once at any time between first study drug intake and cycle 6 (cycle 12 respectively) visit included.

Measure:	Kaplan-Meier Estimates of Duration of First Complete Cytogenic Response (CCyR) Among Patients Who Achieved CCyR in Newly Diagnosed Ph+ CML-CP Patients
Time Frame:	From CCyR to loss of CCyR up to 66 cycles
Safety Issue:
Description:	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 having CCyR by 6 cycles (respectively 12 cycles) if the patient met the CCyR criteria at least once at any time between first study drug intake and cycle 6 (cycle 12 respectively) visit included.

Measure:	Best Major Cytogenetic Response (MCyR) Rate by Time Point in Newly Diagnosed Ph+ CML Patients
Time Frame:	6, 12, 18, 24, 36, 48, 66 cycles
Safety Issue:
Description:	Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.

Measure:	Summary of Time to First Major Cytogenetic Response (MCyR) Among Patients Who Achieved MCyR in Newly Diagnosed CML-CP Patients
Time Frame:	up to 66 cycles
Safety Issue:
Description:	Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.

Measure:	Kaplan-Meier Estimates of Time to First Major Cytogenetic Response (MCyR) in Newly Diagnosed CML-CP Patients
Time Frame:	up to 66 cycles
Safety Issue:
Description:	Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.

Measure:	Best Complete Hematological Response (CHR) by Time Point
Time Frame:	cycle 3, 6, 9, 12, 18, 24, 36, 48, 66
Safety Issue:
Description:	Complete Hematological Response (CHR) was defined as WBC count <10×109/L platelet count <450×109/L basophils <5% no blasts and promyelocytes in peripheral blood myelocytes+metamyelocytes <5% in peripheral blood no evidence of extramedullary disease, including spleen and liver Assessment confirmation after at least 4 weeks for newly diagnosed Ph+ CML-CP

Measure:	Summary of Time to First Complete Hematological Response (CHR) Among Patients Who Achieved Confirmed CHR in Newly Diagnosed CML-CP Patients
Time Frame:	from first dosing to CHR, UP TO 66 CYCLES
Safety Issue:
Description:	Complete Hematological Response (CHR) was defined as WBC count <10×109/L platelet count <450×109/L basophils <5% no blasts and promyelocytes in peripheral blood myelocytes+metamyelocytes <5% in peripheral blood no evidence of extramedullary disease, including spleen and liver Assessment confirmation after at least 4 weeks for newly diagnosed Ph+ CML-CP

Measure:	Kaplan-Meier Estimates of Time to First Complete Hematological Response (CHR) in Newly Diagnosed CML-CP Patients
Time Frame:	from first dosing to CHR, UP TO 66 CYCLES
Safety Issue:
Description:	Complete Hematological Response (CHR) was defined as WBC count <10×109/L platelet count <450×109/L basophils <5% no blasts and promyelocytes in peripheral blood myelocytes+metamyelocytes <5% in peripheral blood no evidence of extramedullary disease, including spleen and liver Assessment confirmation after at least 4 weeks for newly diagnosed Ph+ CML-CP

Measure:	Time to Disease Progression for Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients - Kaplan-Meier Estimates
Time Frame:	From first dosing to the disease progression within 66 cycles
Safety Issue:
Description:	Time to disease progression is the time from the date of first study drug intake to the date of event defined as the first progression to AP or BC (from CP) or to BC (from AP) or the date of CML-related death occurring on treatment, whichever was earlier.

Measure:	Event Free Survival in Imatinib/Dasatinib Resistant/Intolerant CML-CP Patients
Time Frame:	From first dosing to the disease progression or death up to 66 cycles
Safety Issue:
Description:	Event Free Survival is defined as the time from the date of first study drug intake to the first occurrence of any of the following loss of CHR, loss of MCyR ( PCyR + CCyR), progression to AP/BC (from CP) or to BC (from AP), or death from any cause. (Including events only during treatment)

Measure:	Event Free Survival in Newly Diagnosed CML-CP Patients
Time Frame:	From first dosing to the disease progression or death up to 66 cycles
Safety Issue:
Description:	Event Free Survival is defined as the time from the date of first study drug intake to the first occurrence of any of the following loss of CHR, loss of MCyR ( PCyR + CCyR), progression to AP/BC (from CP) or to BC (from AP), or death from any cause. (Including events only during treatment)

Measure:	Overall Survival (OS) in Imatinib/Dasatinib Resistant/Intolerant CML-CP - Kaplan-Meier Estimates
Time Frame:	from first dosing to death up to 66 cycles
Safety Issue:
Description:	Overall survival is defined as the time from the date of first study drug intake to the date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of their last assessment for patients on study and date of last contact for patients in follow-up.

Measure:	Overall Survival (OS) in Newly Diagnosed CML-CP Patients
Time Frame:	from first dosing to death up to 66 cycles
Safety Issue:
Description:	Overall survival is defined as the time from the date of first study drug intake to the date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of their last assessment for patients on study and date of last contact for patients in follow-up.

Measure:	Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle
Time Frame:	By 3, 6, 9, 12, 18, 24, 36, 48, 66 cycles
Safety Issue:
Description:	BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. BCR-ABL transcript levels were summarized by cohort and time point. 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.

Measure:	Pharmacokinetics (PK): Steady State Concentration of Nilotinib in Imatinib/Dasatinib Resistant/Intolerant CML-CP Patients
Time Frame:	Cycle 1 Day 8
Safety Issue:
Description:	PK was analyzed only when all patients has completed 12 cycles on treatment or discontinued the study treatment early.

Measure:	Pharmacokinetics: Steady State Concentration of Nilotinib in Newly Diagnosed CML-CP Patients
Time Frame:	Cycle 1 Day 8
Safety Issue:
Description:	PK was analyzed only when all patients has completed 12 cycles of treatment or discontinued the study treatment early.

Measure:	Growth Data: Abnormal Height Standard Deviation Scores (SDS) Changes by Cohort
Time Frame:	from first dosing to 66 cycles
Safety Issue:
Description:	To assess long term effect on growth, development and maturation of nilotinib treatment in pediatric patients with Ph+ CML in participants with both a baseline and post-baseline value.

Measure:	Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation
Time Frame:	up to Cycle 12
Safety Issue:
Description:	Acceptability of the study drug was evaluated from a questionnaire completed by patients, with the help from parents or caregivers at visits. The Questionnaire to capture patient assessment of palatability (very good to very bad) and acceptability of taking the medication (very easy to very hard to administration).

Measure:	Mutational Assessment of BCR-ABL
Time Frame:	up to 66 cycles
Safety Issue:
Description:	Emerging signs of resistance to nilotinib

Details

Phase:	Phase 2
Primary Purpose:	Interventional
Overall Status:	Completed
Lead Sponsor:	Novartis Pharmaceuticals

Trial Keywords

Tasigna
nilotinib treatment
chronic phase
Ph+ CML
accelerated phase
newly diagnosed Ph+ CML
pediatric
leukemia
leukemia, pediatric
leukemia, myleiod
leukemia, mylegenous, chronic
leukemia, mylegenous, accelerated
BCR-ABL positive
myeloproliferative disorder
bone marrow disease
hematologic diseases
neoplastic processes
imatinib
dasatinib
enzyme inhibitor
protein kinase inhibitor

Last Updated

April 22, 2021

Clinical Trials /

Open Label, Phase II Study to Evaluate Efficacy and Safety of Oral Nilotinib in Philadelphia Positive (Ph+) Chronic Myelogenous Leukemia (CML) Pediatric Patients.