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

Phase 1

Completed

Conditions: Chronic Myeloid Leukemia
Acute Lymphoblastic Leukemia

Interventions: Drug: Nilotinib

Registration Number: NCT01077544

Lead Sponsor: Novartis Pharmaceuticals

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 15

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Group 1	Nilotinib	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.
Group 2	Nilotinib	\>= 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.

Primary Outcome Measures

Name	Time	Method
Summary of Nilotinib Steady-state PK Parameters: AUCss	Cycle 1 Day 8 - Cycle 1 Day 28	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 Non-compartmental PK Parameters: Tmax	Cycle 1 Day 1	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)	Cycle 1 Day 1	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	Cycle 1 Day 1	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: Cmax	Cycle 1 Day 1	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: CLF (Body Surface Area (BSA) Adjusted)	Cycle 1 Day 8 - Cycle 1 day 28	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	Cycle 1 Day 8 - Cycle 1 Day 28	The full PK profiles of nilotinib in pediatric patients were assessed using serial sampling following a single 230 mg/m2 dose.

Secondary Outcome Measures

Name	Time	Method
Number of Ph+ CML Participants With Confirmed Complete Hematologic Response (CHR)	minimum of 12 cycles (28 days per cycle)	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 Major Molecular Response (MMR)	minimum of 12 cycles (28 days per cycle)	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.
Number of Ph+ CML Participants With Cytogenic Response	minimum of 12 cycles (28 days per cycle)	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.
Efficacy Endpoints for Ph+ ALL Patients	minimum of 12 cycles (28 days per cycle)	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.