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

• ClinicalTrials.gov Identifier: NCT01077544
• Recruitment Status: Completed
• First Posted: March 1, 2010
• Results First Posted: January 27, 2016
• Last Update Posted: December 29, 2020
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

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.

Condition or disease	Intervention/treatment	Phase
Chronic Myeloid Leukemia; Acute Lymphoblastic Leukemia	Drug: Nilotinib	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 15 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (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
• Actual Study Start Date: April 14, 2011
• Actual Primary Completion Date: July 1, 2015
• Actual Study Completion Date: July 1, 2015

Arms and Interventions

Arm	Intervention/treatment
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

Outcome Measures

Primary Outcome Measures :

1. Summary of Nilotinib Non-compartmental PK Parameters: Cmax [ Time Frame: 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.
2. Summary of Nilotinib Non-compartmental PK Parameters: Tmax [ Time Frame: 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.
3. Summary of Nilotinib Non-compartmental PK Parameters: AUClast (Last = 24h) [ Time Frame: 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.
4. Summary of Nilotinib Non-compartmental PK Parameters: AUC0-12h [ Time Frame: 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.
5. Summary of Nilotinib Steady-state PK Parameters: AUCss [ Time Frame: 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
6. Summary of Nilotinib Steady-state PK Parameters: CLF (Body Surface Area (BSA) Adjusted) [ Time Frame: 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
7. Summary of Nilotinib Steady-state PK Parameters: Cmin [ Time Frame: 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 :

1. Number of Ph+ CML Participants With Confirmed Complete Hematologic Response (CHR) [ Time Frame: 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.
2. Number of Ph+ CML Participants With Cytogenic Response [ Time Frame: 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.
3. Number of Ph+ CML Participants With Major Molecular Response (MMR) [ Time Frame: 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.
4. Efficacy Endpoints for Ph+ ALL Patients [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 1 Year to 17 Years (Child)
• Sexes Eligible for Study: All
• 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

Locations

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

Netherlands

Novartis Investigative Site

Amsterdam, Netherlands, 1081 HV

Novartis Investigative Site

Rotterdam, Netherlands, 3015 CN

United Kingdom

Novartis Investigative Site

West Midlands, Birmingham, United Kingdom, B4 6NH

Novartis Investigative Site

Sutton, Surrey, United Kingdom, SM2 5PT

Novartis Investigative Site

Bristol, United Kingdom, BS2 8BJ

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

More Information

Additional Information:

Results for CAMN107A2120 can be found on the Novartis Clinical Trial Results Website 

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01077544
• Other Study ID Numbers: CAMN107A2120; 2010-018419-14 ( EudraCT Number )
• First Posted: March 1, 2010
• Results First Posted: January 27, 2016
• Last Update Posted: December 29, 2020
• Last Verified: October 2020

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

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; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases