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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)

Primary Purpose

Chronic Myeloid Leukemia, Acute Lymphoblastic Leukemia

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Nilotinib
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Myeloid Leukemia focused on measuring Chronic Myeloid Leukemia, Acute Lymphoblastic Leukemia, Ph+ CML, Ph+ ALL, pediatric, nilotinib, imatinib, chronic phase, accelerated phase, newly diagnosed Ph+ CML, dasatinib

Eligibility Criteria

1 Year - 17 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Group 1

Group 2

Arm Description

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.

>= 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.

Outcomes

Primary Outcome Measures

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.
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.
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.
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.
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
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
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.

Secondary Outcome Measures

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.
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.
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.
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.

Full Information

First Posted
February 26, 2010
Last Updated
December 6, 2020
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01077544
Brief Title
A Pharmacokinetic (PK) Study of Nilotinib in Pediatric Patients With Philadelphia Chromosome-positive (Ph+) Chronic Myelogenous Leukemia (CML) or Acute Lymphoblastic Leukemia (ALL)
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2020
Overall Recruitment Status
Completed
Study Start Date
April 14, 2011 (Actual)
Primary Completion Date
July 1, 2015 (Actual)
Study Completion Date
July 1, 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Myeloid Leukemia, Acute Lymphoblastic Leukemia
Keywords
Chronic Myeloid Leukemia, Acute Lymphoblastic Leukemia, Ph+ CML, Ph+ ALL, pediatric, nilotinib, imatinib, chronic phase, accelerated phase, newly diagnosed Ph+ CML, dasatinib

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group 1
Arm Type
Experimental
Arm Description
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.
Arm Title
Group 2
Arm Type
Experimental
Arm Description
>= 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.
Intervention Type
Drug
Intervention Name(s)
Nilotinib
Other Intervention Name(s)
AMN107
Intervention Description
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.
Primary Outcome Measure Information:
Title
Summary of Nilotinib Non-compartmental PK Parameters: Cmax
Description
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
Title
Summary of Nilotinib Non-compartmental PK Parameters: Tmax
Description
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
Title
Summary of Nilotinib Non-compartmental PK Parameters: AUClast (Last = 24h)
Description
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
Title
Summary of Nilotinib Non-compartmental PK Parameters: AUC0-12h
Description
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
Title
Summary of Nilotinib Steady-state PK Parameters: AUCss
Description
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
Title
Summary of Nilotinib Steady-state PK Parameters: CLF (Body Surface Area (BSA) Adjusted)
Description
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
Title
Summary of Nilotinib Steady-state PK Parameters: Cmin
Description
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
Secondary Outcome Measure Information:
Title
Number of Ph+ CML Participants With Confirmed Complete Hematologic Response (CHR)
Description
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)
Title
Number of Ph+ CML Participants With Cytogenic Response
Description
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)
Title
Number of Ph+ CML Participants With Major Molecular Response (MMR)
Description
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)
Title
Efficacy Endpoints for Ph+ ALL Patients
Description
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)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Novartis Investigative Site
City
Bordeaux
State/Province
Aquitaine
ZIP/Postal Code
33076
Country
France
Facility Name
Novartis Investigative Site
City
Lille cedex
ZIP/Postal Code
59037
Country
France
Facility Name
Novartis Investigative Site
City
Paris
ZIP/Postal Code
75571
Country
France
Facility Name
Novartis Investigative Site
City
Poitiers
ZIP/Postal Code
86021
Country
France
Facility Name
Novartis Investigative Site
City
Monza
State/Province
MB
ZIP/Postal Code
20900
Country
Italy
Facility Name
Novartis Investigative Site
City
Padova
State/Province
PD
ZIP/Postal Code
35128
Country
Italy
Facility Name
Novartis Investigative Site
City
Roma
State/Province
RM
ZIP/Postal Code
00161
Country
Italy
Facility Name
Novartis Investigative Site
City
Amsterdam
ZIP/Postal Code
1081 HV
Country
Netherlands
Facility Name
Novartis Investigative Site
City
Rotterdam
ZIP/Postal Code
3015 CN
Country
Netherlands
Facility Name
Novartis Investigative Site
City
West Midlands
State/Province
Birmingham
ZIP/Postal Code
B4 6NH
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
Sutton
State/Province
Surrey
ZIP/Postal Code
SM2 5PT
Country
United Kingdom
Facility Name
Novartis Investigative Site
City
Bristol
ZIP/Postal Code
BS2 8BJ
Country
United Kingdom

12. IPD Sharing Statement

Links:
URL
https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=14405
Description
Results for CAMN107A2120 can be found on the Novartis Clinical Trial Results Website

Learn more about this trial

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

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