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

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ClinicalTrials.gov Identifier: NCT01844765
Recruitment Status : Active, not recruiting
First Posted : May 1, 2013
Results First Posted : May 21, 2018
Last Update Posted : May 21, 2018
Sponsor:
Collaborators:
Children's Oncology Group
Innovative Therapies For Children with Cancer Consortium
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
To evaluate the safety, efficacy and concentration of nilotinib over time in the Ph+ chronic myelogenous leukemia (CML) in pediatric patients (from 1 to <18 years).

Condition or disease Intervention/treatment Phase
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 Drug: nilotinib Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 59 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : August 20, 2013
Actual Primary Completion Date : June 1, 2016
Estimated Study Completion Date : October 7, 2020


Arm Intervention/treatment
Experimental: 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.
Drug: nilotinib
Nilotinib supplied in 50mg, 150mg, and 200mg capsules. It was administered at 230mg/m2, twice daily for up to 66 cycles (1 cycle = 28 days). Dose administration was rounded to the nearest 50mg dose (to a maximum dose of 400mg).
Other Name: AMN107

Experimental: Resistant/intolerant Ph+ CML in CP
Resistant or Intolerant to either imatnib or dasatnib
Drug: nilotinib
Nilotinib supplied in 50mg, 150mg, and 200mg capsules. It was administered at 230mg/m2, twice daily for up to 66 cycles (1 cycle = 28 days). Dose administration was rounded to the nearest 50mg dose (to a maximum dose of 400mg).
Other Name: AMN107

Experimental: Resistant/intolerant Ph+ CML in AP
Resistant or intolerant to either imatnib or dasatnib - at the point of reporting interim results, no patients were enrolled in this arm.
Drug: nilotinib
Nilotinib supplied in 50mg, 150mg, and 200mg capsules. It was administered at 230mg/m2, twice daily for up to 66 cycles (1 cycle = 28 days). Dose administration was rounded to the nearest 50mg dose (to a maximum dose of 400mg).
Other Name: AMN107




Primary Outcome Measures :
  1. 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.

  2. 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.

  3. 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 Outcome Measures :
  1. CCyR Rate by Cycles 6 and 12 in Newly Diagnosed Ph+ CML-CP Patients [ Time Frame: 6 & 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 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.

  2. MMR Rate by Time Points in Newly Diagnosed Ph+ CML-CP Patients [ Time Frame: by 3, 6, 9 and 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 a time point if the patient met the MMR criteria at least once at any time between first study drug intake and the time point visit included.

  3. Time to First MMR Among Newly Diagnosed Ph+ CML-CP Patients Who Achieved MMR [ Time Frame: From first dose of study treatment until MMR criteria are met (Assessed up to June 2016, minimum of 12 cycles) ]
    Time to MMR is the time from first study drug intake to first major molecular response computed only for participants who achieved MMR.

  4. Duration of First MMR Among Newly Diagnosed Patients Who Achieved MMR [ Time Frame: from MMR until confirmed loss of MMR (Assessed up to June 2016, minimum of 12 cycles) ]
    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.

  5. MMR Rate by Time Points in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib [ Time Frame: By 3, 6, 9 & 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 a time point if the patient met the MMR criteria at least once at any time between first study drug intake and the time point visit included.

  6. Time to First MMR Among Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients Who Achieved MMR [ Time Frame: From first dose of study treatment until MMR criteria are met (Assessed up to June 2016, minimum of 12 cycles) ]
    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.

  7. 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 June 2016, minimum of 12 cycles) ]
    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.

  8. Cumulative Best BCR-ABL Ratio Categories for Resistant/Intolerant Ph+ CML in CP by 6 and 12 Cycles [ Time Frame: minimum of 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. 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)

  9. Cumulative Best BCR-ABL Ratio Categories for Newly Diagnosed Ph+ CML-CP by 6 and 12 Cycles [ Time Frame: minimum of 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. 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)

  10. Time to Disease Progression for Newly Diagnosed Ph+ CML-CP [ Time Frame: up to disease progression (assessed up to a minimum of 12 cycles after first dose of treatment (June 2016)) ]
    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.

  11. Time to Disease Progression for Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients [ Time Frame: up to disease progression (assessed up to a minimum of 12 cycles after first dose of treatment (June 2016)) ]
    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.

  12. Overall Survival (OS) [ Time Frame: up to 66 cycles ]
    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.

  13. Pharmacodynamics [ Time Frame: up to 66 cycles ]
    BCR-ABL transcript levels determined with standard protocols in peripheral blood and bone marrow for all time points with available data

  14. Event Free Survival [ Time Frame: up to 66 cycles ]
    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)

  15. Rate of Cytogenetic Response Category [ Time Frame: 6, 12, 18, 24, 36, 48, 66 cycles ]
    Rate of cytogenetic response (complete, partial, major, minor, minimal and no response) in Ph+ CML-CP resistant/intolerant to imatinib or dasatinib by 6, 12, 18,24, 36, 48 and 66 cycles

  16. PK Profile of Nilotinib in Pediatric Patients [ Time Frame: up to 12 cycles ]
    Population PK parameters of nilotinib

  17. Emerging Signs of Resistance [ Time Frame: up to 66 cycles ]
    Mutational assessment of BCR-ABL

  18. Long Term Effect of Nilotinib on Growth, Development and Maturation [ Time Frame: up to 66 cycles ]
    Assessment of development (growth and sexual maturation) and thyroid function

  19. Acceptability of Study Drug Formulation [ Time Frame: day1, day 28, early discontinuation or month 12 ]
    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).

  20. Rate of Major Cytogenetic Response (MCyR) and Confirmed Cytogenetic Response (CCyR) in Newly Diagnosed Ph+ CML and in Ph+ CML-AP Patients Resistant/Intolerant to Either Imatinib or Dasatinib [ Time Frame: 6, 12, 18, 24, 36, 48, 66 cycles ]
    Rate of major cytogenetic response (MCyR) and confirmed cytogenetic response (CCyR) in Newly diagnosed Ph+ CML and in Ph+ CML-AP patients resistant/intolerant to either imatinib or dasatinib by designated timepoints


Other Outcome Measures:
  1. Long Term Effect on Nilotinib on Bone Metabolism [ Time Frame: up to 66 cycles ]
    Alteration of bone biochemical markers, DEXA and X-Ray



Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 or Lansky ≥ 50
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01844765


  Show 36 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Children's Oncology Group
Innovative Therapies For Children with Cancer Consortium
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01844765     History of Changes
Other Study ID Numbers: CAMN107A2203
2013-000200-41 ( EudraCT Number )
First Posted: May 1, 2013    Key Record Dates
Results First Posted: May 21, 2018
Last Update Posted: May 21, 2018
Last Verified: April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com


Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Tasigna
nilotinib treatment
chronic phase
Ph+ CML
accelerated phase
newly diagnosed Ph+ CML
pediatric
24 month treatment

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Myeloproliferative Disorders
Hematologic Diseases
Bone Marrow Diseases
Neoplastic Processes
Neoplasms by Histologic Type
Neoplasms
Pathologic Processes