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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01077544
First received: February 26, 2010
Last updated: December 18, 2015
Last verified: December 2015
  Purpose
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.

Condition Intervention Phase
Chronic Myeloid Leukemia
Acute Lymphoblastic Leukemia
Drug: Nilotinib
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Multi-center, Open-label, Pharmacokinetic Study of Oral Nilotinib in Pediatric Patients With Newly Diagnosed Chronic Phase (CP) Ph+ CML, With CP or Accelerated Phase (AP) Ph+ CML Resistant/Intolerant to Imatinib and/or Dasatinib, or With Refractory/Relapsed Ph+ ALL

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Summary of Nilotinib Non-compartmental PK Parameters: Cmax [ Time Frame: Cycle 1 Day 1 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1 Day 1 ] [ Designated as safety issue: No ]
    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: AUClast (Last = 24h) [ Time Frame: Cycle 1 Day 1 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1 Day 1 ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1 Day 8 - Cycle 1 Day 28 ] [ Designated as safety issue: No ]
    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) [ Time Frame: Cycle 1 Day 8 - Cycle 1 day 28 ] [ Designated as safety issue: No ]
    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: Cmin [ Time Frame: Cycle 1 Day 8 - Cycle 1 Day 28 ] [ Designated as safety issue: No ]
    The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose.


Secondary Outcome Measures:
  • Number of Ph+ CML Participants With Confirmed Complete Hematologic Response (CHR) [ Time Frame: minimum of 12 cycles (28 days per cycle) ] [ Designated as safety issue: No ]
    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.

  • Number of Ph+ CML Participants With Cytogenic Response [ Time Frame: minimum of 12 cycles (28 days per cycle) ] [ Designated as safety issue: No ]
    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) [ Time Frame: minimum of 12 cycles (28 days per cycle) ] [ Designated as safety issue: No ]
    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 [ Time Frame: minimum of 12 cycles (28 days per cycle) ] [ Designated as safety issue: No ]
    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.


Enrollment: 15
Study Start Date: April 2011
Study Completion Date: July 2015
Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group 1
1 year to < 10 years pediatric patients with newly diagnosed CP-Ph+ CML, or CP or AP-Ph+ CML resistant/intolerant to imatinib and/or dasatinib, or relapsed/refractory Ph+ ALL (acute lymphoblastic leukemia) treated at the proposed dose of 230 mg/m2 bid.
Drug: Nilotinib

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.

Other Name: AMN107
Experimental: Group 2
>= 10 years to <18 years pediatric patients with newly diagnosed CP-Ph+ CML, or CP or AP-Ph+ CML resistant/intolerant to imatinib and/or dasatinib, or relapsed/refractory Ph+ ALL (acute lymphoblastic leukemia) treated at the proposed dose of 230 mg/m2 bid.
Drug: Nilotinib

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.

Other Name: AMN107

  Eligibility

Ages Eligible for Study:   1 Year to 18 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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/exclusion criteria may apply

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01077544

Locations
United States, Illinois
Ann & Robert H. Lurie Children's Hospital of Chicago Ann&Robert Lurie
Chicago, Illinois, United States, 60611
Brazil
Novartis Investigative Site
Barretos, SP, Brazil, 14784-400
Novartis Investigative Site
Sao Paulo, SP, Brazil
Novartis Investigative Site
São Paulo, SP, Brazil, 08270-070
France
Novartis Investigative Site
Bordeaux, Aquitaine, France, 33076
Novartis Investigative Site
Lille cedex, France, 59037
Novartis Investigative Site
Paris, France, 75571
Novartis Investigative Site
Poitiers, France, 86021
Italy
Novartis Investigative Site
Monza, MB, Italy, 20900
Novartis Investigative Site
Padova, PD, Italy, 35128
Novartis Investigative Site
Roma, RM, Italy, 00161
Korea, Republic of
Novartis Investigative Site
Seoul, Korea, Korea, Republic of, 110 744
Netherlands
Novartis Investigative Site
Amsterdam, Netherlands, 1081 HV
Novartis Investigative Site
Rotterdam, Netherlands, 3015 GJ
Russian Federation
Novartis Investigative Site
Moscow, Russian Federation, 117997
United Kingdom
Novartis Investigative Site
Sutton, Surrey, United Kingdom, SM2 5PT
Novartis Investigative Site
Birmingham, United Kingdom, B4 6NH
Novartis Investigative Site
Bristol, United Kingdom, BS2 8BJ
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01077544     History of Changes
Other Study ID Numbers: CAMN107A2120  2010-018419-14 
Study First Received: February 26, 2010
Results First Received: December 18, 2015
Last Updated: December 18, 2015
Health Authority: United States: Food and Drug Administration
European Union: European Medicines Agency
Italy: Italian Medicines Agency (AIFA)
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Netherlands: Centrale Commissie Mensgebonden Onderzoek (CCMO)
Russia: Ministry of Health of the Russian Federation
France: ANSM
Thailand: Food and Drug Administration
Brazil: ANVISA - Agência Nacional de Vigilância Sanitária
Germany: Federal Institute for Drugs & Medical Devices
Korea: MFDS Ministry of Food & Drug Safety

Keywords provided by Novartis:
Chronic Myeloid Leukemia
Acute Lymphoblastic Leukemia
Ph+ CML
Ph+ ALL
pediatric
nilotinib
imatinib
chronic phase
accelerated phase
newly diagnosed Ph+ CML
dasatinib

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Philadelphia Chromosome
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Translocation, Genetic
Chromosome Aberrations
Pathologic Processes
Dasatinib
Imatinib Mesylate
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on September 30, 2016