Clinical trial NCT01844765: Open Label, Phase II Study to Evaluate Efficacy and Safety of Oral Nilotinib in Philadelphia Positive (Ph+) Chronic Myelogenous Leukemia (CML) Pediatric Patients.
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Philadelphia Positive (Ph+) Chronic Myelogenous Leukemia
Keywords: Tasigna
nilotinib treatment
chronic phase
Ph+ CML
accelerated phase
newly diagnosed Ph+ CML
pediatric
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
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2013-05-01
Enrollment: 59
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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

Detailed description: The study was designed as a multi-center, open-label, non-controlled phase II study to assess efficacy, safety and PK parameters of 230 mg/m2 twice daily nilotinib in pediatric patients (1 to \<18 years old). The study population consisted of three cohorts of Ph+ CML pediatric patients:

* Cohort 1: Ph+ CML-CP patients resistant or intolerant to either imatinib or dasatinib
* Cohort 2: Ph+ CML-AP patients resistant or intolerant to either imatinib or dasatinib
* Cohort 3: Newly-diagnosed Ph+ CML-CP patients in first chronic phase A minimum number of 50 pediatric patients (from 1 to \<18 years) were enrolled in the study. Of them, at least 15 patients were Ph+ CML-CP patients resistant or intolerant to either imatinib or dasatinib, and at least 15 were newly-diagnosed Ph+ CML-CP patients in first chronic phase patients. There was no minimum number of patients required for Ph+ CML-AP patients resistant or intolerant to either imatinib or dasatinib.

Based on enrollment forecasts as of Jan 2015, and to reflect the agreements with the US FDA and the PDCO, the study remained open for enrollment until the targeted number of 50 patients with at least 15 newly diagnosed Ph+CML patients was achieved or until 31May2015, whichever was later.

Patients who completed the study were treated with nilotinib for a total of 66 cycles of 28 days unless the patient prematurely discontinued study treatment.

The primary analysis cut-off date was the date when all patients enrolled in the trial either completed their visit for treatment cycle 12 or had discontinued study treatment early (EoT/early discontinuation visit). These analyses were reported in the 12-cycle clinical study report (CSR). A 24-cycle analysis was done when all patients had either completed their 24-cycle treatment visit or had discontinued study treatment early.

At trial end, a final comprehensive CSR of all data collected during the trial was produced.

Eligibility criteria: Key Inclusion Criteria:

* Newly diagnosed and untreated Ph+ CML CP or Ph+ CML CP or AP resistant or intolerant to either imatinib or dasatinib
* Karnofsky ≥ 50% for patients \> 10 years of age and Lansky ≥ 50 for patients ≤ 10 years of age
* Adequate renal, hepatic and pancreatic function
* Potassium, magnesium, phosphorus and total calcium values ≥ LLN (lower limit of normal)
* Written informed consent

Key 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.
* the criteria regarding pregnancy and contraception
* Active or systemic bacterial, fungal, or viral infection
* known Hepatitis B, Hepatitis C, or HIV infection

Primary outcomes:
measure: Rate of Major Molecular Response (MMR) at 6 Cycles for Ph+ CML CP Patients Resistant or Intolerant to Imatinib or Dasatinib
timeFrame: 6 cycles
measure: MMR Rate by 12 Cycles in Newly Diagnosed Ph+ CML-CP Patients
timeFrame: 12 cycles
measure: Rate of Complete Cytogenic Response (CCyR) at 12 Cycles in Newly Diagnosed Ph+ CML-CP Patients
timeFrame: 12 cycles
Secondary outcomes:
measure: MMR Rate by Time Points in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib
timeFrame: By 3, 6, 9 , 12, 24, 36, 48, 66 cycles ( 1 cycle = 28 days)
measure: MMR Rate by Time Points in Newly Diagnosed Ph+ CML-CP Patients
timeFrame: by 3, 6, 9, 12, 24, 36, 48, 66 cycles (1 cycle = 28 days)
measure: Best BCR-ABL Ratio Categories for Resistant/Intolerant Ph+ CML - Overall
timeFrame: up to 66 cycles (1 cycle = 28 days)
measure: Best BCR-ABL Ratio Categories for Newly Diagnosed Ph+ CML-CP - Overall
timeFrame: up to 66 cycles (1 cycle = 28 days)
measure: Time to First MMR Among Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients Who Achieved MMR
timeFrame: From first dosing to the first MMR within 66 cycles period
measure: Time to First MMR Among Newly Diagnosed Ph+ CML-CP Patients Who Achieved MMR
timeFrame: From first dosing to the first MMR within 66 cycles period
measure: Duration of First MMR Among Patients Who Were Resistant or Intolerant to Either Imatinib or Dasatinib Who Achieved MMR
timeFrame: from MMR until confirmed loss of MMR (Assessed up to 66 cycles)
measure: Duration of First MMR Among Newly Diagnosed Patients Who Achieved MMR
timeFrame: from MMR until confirmed loss of MMR (Assessed up to 66 cycles)es)
measure: Best Complete Cytogenetic Response (CCyR) Categories in Ph+ CML-CP Patients Resistant or Intolerant to Imatinib or Dasatinib - Overall
timeFrame: up to 66 cycles
measure: Best Complete Cytogenetic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients - Overall
timeFrame: up to 66 cycles
measure: Summary of Time to First Complete Cytogenic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients
timeFrame: From first dosing to the first CCyR up to 66 cycles
measure: Kaplan-Meier Estimates of Time to First Complete Cytogenic Response (CCyR) in Newly Diagnosed Ph+ CML-CP Patients
timeFrame: From first dosing to the first CCyR up to 66 cycles
measure: Kaplan-Meier Estimates of Duration of First Complete Cytogenic Response (CCyR) Among Patients Who Achieved CCyR in Newly Diagnosed Ph+ CML-CP Patients
timeFrame: From CCyR to loss of CCyR up to 66 cycles
measure: Best Major Cytogenetic Response (MCyR) Rate by Time Point in Newly Diagnosed Ph+ CML Patients
timeFrame: 6, 12, 18, 24, 36, 48, 66 cycles
measure: Summary of Time to First Major Cytogenetic Response (MCyR) Among Patients Who Achieved MCyR in Newly Diagnosed CML-CP Patients
timeFrame: up to 66 cycles
measure: Kaplan-Meier Estimates of Time to First Major Cytogenetic Response (MCyR) in Newly Diagnosed CML-CP Patients
timeFrame: up to 66 cycles
measure: Best Complete Hematological Response (CHR) by Time Point
timeFrame: cycle 3, 6, 9, 12, 18, 24, 36, 48, 66
measure: Summary of Time to First Complete Hematological Response (CHR) Among Patients Who Achieved Confirmed CHR in Newly Diagnosed CML-CP Patients
timeFrame: from first dosing to CHR, UP TO 66 CYCLES
measure: Kaplan-Meier Estimates of Time to First Complete Hematological Response (CHR) in Newly Diagnosed CML-CP Patients
timeFrame: from first dosing to CHR, UP TO 66 CYCLES
measure: Time to Disease Progression for Imatinib or Dasatinib Resistant or Intolerant CML-CP Patients - Kaplan-Meier Estimates
timeFrame: From first dosing to the disease progression within 66 cycles
measure: Event Free Survival in Imatinib/Dasatinib Resistant/Intolerant CML-CP Patients
timeFrame: From first dosing to the disease progression or death up to 66 cycles
measure: Event Free Survival in Newly Diagnosed CML-CP Patients
timeFrame: From first dosing to the disease progression or death up to 66 cycles
measure: Overall Survival (OS) in Imatinib/Dasatinib Resistant/Intolerant CML-CP - Kaplan-Meier Estimates
timeFrame: from first dosing to death up to 66 cycles
measure: Overall Survival (OS) in Newly Diagnosed CML-CP Patients
timeFrame: from first dosing to death up to 66 cycles
measure: Pharmacodynamics (BCR-ABL Transcript Levels Determined With Standard Protocols in Peripheral Blood): Best MMR Status by Cycle
timeFrame: By 3, 6, 9, 12, 18, 24, 36, 48, 66 cycles
measure: Pharmacokinetics (PK): Steady State Concentration of Nilotinib in Imatinib/Dasatinib Resistant/Intolerant CML-CP Patients
timeFrame: Cycle 1 Day 8
measure: Pharmacokinetics: Steady State Concentration of Nilotinib in Newly Diagnosed CML-CP Patients
timeFrame: Cycle 1 Day 8
measure: Growth Data: Abnormal Height Standard Deviation Scores (SDS) Changes by Cohort
timeFrame: from first dosing to 66 cycles
measure: Acceptability (Including Palatability) of Dose Forms Used After First Dose, Cycle 1 and Cycle 12 Study Drug Formulation
timeFrame: up to Cycle 12
measure: Mutational Assessment of BCR-ABL
timeFrame: up to 66 cycles
Other outcomes:
measure: Long Term Effect of Nilotinib on Bone Metabolism
timeFrame: Cycle 66
Locations:
city: Loma Linda
country: United States
facility: Loma Linda University Cancer Center
state: California
city: Palo Alto
country: United States
facility: Lucile Salter Packard Children's Hospital at Stanford
state: California
city: Orlando
country: United States
facility: Nemours Childrens Hospital
state: Florida
city: West Palm Beach
country: United States
facility: St. Mary's Hospital
state: Florida
city: Baltimore
country: United States
facility: Johns Hopkins Oncology Center ORA
state: Maryland
city: Chapel Hill
country: United States
facility: UNC Chapel Hill
state: North Carolina
city: Columbus
country: United States
facility: Nationwide Childrens Hospital
state: Ohio
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center Oncology
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center Oncology
state: Texas
city: Seattle
country: United States
facility: Seattle Childrens Hospital
state: Washington
city: Bordeaux
country: France
facility: Novartis Investigative Site
state: Aquitaine
city: Lille
country: France
facility: Novartis Investigative Site
city: Paris Cedex
country: France
facility: Novartis Investigative Site
city: Poitiers
country: France
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Monza
country: Italy
facility: Novartis Investigative Site
state: MB
city: Padova
country: Italy
facility: Novartis Investigative Site
state: PD
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Yokohama-city
country: Japan
facility: Novartis Investigative Site
state: Kanagawa
city: Sakyo Ku
country: Japan
facility: Novartis Investigative Site
state: Kyoto
city: Shinjuku-ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Saitama
country: Japan
facility: Novartis Investigative Site
city: Shizuoka
country: Japan
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Kuala Lumpur
country: Malaysia
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Moscow
country: Russian Federation
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Muang
country: Thailand
facility: Novartis Investigative Site
state: Chiangmai
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Bangkok
country: Thailand
facility: Novartis Investigative Site
city: Istanbul
country: Turkey
facility: Novartis Investigative Site
city: Sutton
country: United Kingdom
facility: Novartis Investigative Site
state: Surrey
city: Bristol
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Hijiya N, Maschan A, Rizzari C, Shimada H, Dufour C, Goto H, Kang HJ, Guinipero T, Karakas Z, Bautista F, Ducassou S, Yoo KH, Zwaan CM, Millot F, Patterson B, Samis J, Aimone P, Allepuz A, Titorenko K, Sosothikul D. A phase 2 study of nilotinib in pediatric patients with CML: long-term update on growth retardation and safety. Blood Adv. 2021 Jul 27;5(14):2925-2934. doi: 10.1182/bloodadvances.2020003759.
citation: Hijiya N, Maschan A, Rizzari C, Shimada H, Dufour C, Goto H, Kang HJ, Guinipero T, Karakas Z, Bautista F, Ducassou S, Yoo KH, Zwaan CM, Millot F, Aimone P, Allepuz A, Quenet S, Hourcade-Potelleret F, Hertle S, Sosothikul D. Phase 2 study of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia. Blood. 2019 Dec 5;134(23):2036-2045. doi: 10.1182/blood.2019000069.