E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
pediatric patients with newly diagnosed chronic phase (CP) Ph+ CML, with CP or accelerated phase (AP) Ph+ CML imatinib resistant / intolerant to imatinib and/or dasatinib, or with Ph+ CML chronic phase (CP) or accelerated phase (AP) or with refractory / relapsed Ph+ ALL. |
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E.1.1.1 | Medical condition in easily understood language |
patients below 18 years who have a specific form of leukemia, in more detail Gleevec®-resistant/intolerant form of chronic myelogenous leukemia or with a specific form of refractory/relapsed ALL |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009700 |
E.1.2 | Term | CML |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To characterize the PK of nilotinib in pediatric patients with newly diagnosed CP Ph+ CML, with CP or AP Ph+ CML resistant/intolerant to imatinib and/or dasatinib, or with imatinib resistant / intolerant Ph+ CML CP or AP and Ph+ ALL refractory / relapsed to standard therapy. |
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E.2.2 | Secondary objectives of the trial |
•To assess the safety and tolerability of nilotinib. •To assess the pharmacodynamics of nilotinib by its activity (hematologic, cytogenetic and molecular responses). •To assess mutations in BCR-ABL at baseline and at the end of study.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Male or female patients less than 18 years and more than 1 year of age at study entry. 2.Written informed consent, according to local guidelines, signed by the patients and / or by the parents or legal guardian prior to any study related screening procedures are performed. 3.Patients must have one of the following: newly diagnosed CP Ph+ CML,or CP or AP Ph+ CML resistant/ intolerant to imatinib and/or dasatinib, or Ph+ CML CP or AP or Ph+ ALL either relapsed after or refractory to standard therapy. a. Imatinib or dasatinib resistance in Ph+ CML is defined as: • Increasing WBC or platelet count while on imatinib or dasatinib therapy indicative of a hematological relapse or primary resistance to imatinib or dasatinib. • Cytogenetic or molecular response consistent with suboptimal response or failure criteria adapted from ELN (European Leukemia Net) recommendations • Progression to accelerated phase or blast crisis while on imatinib or dasatinib therapy. • Reappearance of Ph+ bone marrow cells after a complete cytogenetic response to imatinib or dasatinib. • A greater than 30% increase in Ph+ cells in peripheral blood or on bone marrow cytogenetics while on imatinib or dasatinib therapy. • Loss of molecular response on imatinib or dasatinib therapy. b. Imatinib/dasatinib intolerance (at any dose or duration) is defined as the development of AEs requiring discontinuation of imatinib or dasatinib therapy. c. Newly diagnosed CP Ph+ CML is defined as: • Patients with Ph+ CML-CP within 6 months of diagnosis (date of initial diagnosis is the date of first cytogenetic analysis). • Diagnosis of chronic myelogenous leukemia in chronic phase with cytogenetic confirmation of Philadelphia chromosome with (9;22)translocation (to confirm the presence of BCR-ABL and review of a minimum 20 metaphases is required). Standard conventional cytogenetic analysis must be done on bone marrow. FISH cannot be used for study purposes. 4.Performance status: Karnofsky ≥ 50% for patients > 10 years of age, and Lansky ≥ 50 for patients ≤ 10 years of age. 5.Patients must have adequate renal, hepatic and pancreatic function defined as: •Creatinine clearance or radioisotope GFR 70 ml/min/1.73 m2, or a serum creatinine based on age as described in protocol •Total bilirubin (sum of conjugated + unconjugated) 1.5 x upper limit of normal (ULN) for age. •Serum amylase and lipase ≤ 1.5 x ULN •SGPT (ALT) and SGOT (AST) 2 x upper limit of normal (ULN) for age. 6.Female patients of childbearing potential must have a negative serum pregnancy test within 7 days before initiation of study drug. Women of child-bearing potential, defined as all women physiologically capable and becoming pregnant, must use a highly effective method of contraception during dosing and for up to 7 days after last dose of study drug. Acceptable methods of birth control include total abstinence and male/female sterilization or a combination of any two of the following (a+b or a+c or b+c): a. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormonal vaginal ring or transdermal hormone contraception. b. Placement of an intrauterine device (IUD) or intrauterine system (IUS). c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel, cream, vaginal suppository. 7.Patients must have the following laboratory values (≥LLN (lower limit of normal)) or corrected to within normal limits with supplements prior to the first dose of study medication): •Potassium ≥ LLN •Magnesium ≥ LLN •Phosphorus ≥ LLN •Total calcium (corrected for serum albumin) ≥ LLN
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E.4 | Principal exclusion criteria |
1.Patients actively receiving therapy with strong CYP3A4 inhibitors and inducers and the treatment cannot be either discontinued or switched to a different medication at least 14 days prior to starting study drug. 2.Patients who are currently receiving treatment with any medications that have 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. A list of QT prolonging compounds can be found at http://www.azcert.org/medical-pros/drug-lists/printable-drug-list.cfm. 3.Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug(e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, mal-absorption, small bowel resection, or gastric bypass surgery). 4.Acute or chronic liver, pancreatic or severe renal disease considered unrelated to CML or ALL. 5.History of pancreatitis within 12 months of starting study drug or past medical history of chronic pancreatitis. 6.No active or systemic bacterial, fungal, or viral infection as documented by positive cultures, radiological imaging techniques, or septic shock syndrome. 7.Impaired cardiac function including any one of the following: •Inability to determine the QT interval on ECG •Complete left bundle branch block •Use of a ventricular-paced pacemaker •Congenital long QT syndrome or a known family history of long QT syndrome. •History of or presence of clinically significant ventricular or atrial tachyarrhythmias •Clinically significant resting brachycardia (<50 beats per minute) •QTcF > 450 msec on baseline ECG (using the QTcF formula). If QTcF >450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTcF •History of clinically documented myocardial infarction within 12 months of starting study drug. •History of unstable angina within 12 months of starting study drug. •Other clinically significant heart disease (e.g. congestive heart failure or uncontrolled hypertension). 8.Patients who have received dasatinib therapy within 3 days of starting study drug. 9.Patients who have received imatinib therapy within 5 days of starting study drug. 10.a)Patients who have received myelosuppressive chemotherapy within 14 days prior to first dose of study drug. b)Patients who have not recovered from all acute toxicities from all prior myelosuppressive chemotherapy to ≤ Grade 1 (except alopecia) prior to starting study drug. 11. Patients receiving greater than 14 days of hydroxyurea for the treatment of Ph+ CML or corticosteroids for the treatment of Ph+ ALL and has not been discontinued at least one week after the initiation of nilotinib (see Section 6.6.4 for details on permitted concomitant use of hydroxyurea and corticosteroids). 12. a) Patients who have received hematopoietic growth factors within 7 days of starting study drug b) Patients who have received Pegfligrastim (Neulasta®) within 14 days of starting study drug. 13.Stem Cell Transplant (SCT) or Rescue without total body irradiation (TBI): Evidence of active graft vs. host disease, and < 3 months since SCT. 14.External beam radiation therapy (XRT): •< 2 weeks after local palliative XRT (small port) •< 3 months after prior total body irradiation, or craniospinal radiation, or if ≥ 50% radiation of pelvis was treated with radiation therapy •< 6 weeks after other substantial BM irradiation 15.Patients with a known T315I mutation in BCR-ABL. 16.Patients with known Hepatitis B, Hepatitis C, or HIV infection. 17.Patients who, in the opinion of the investigator, are unlikely to comply with the protocol or safety monitoring requirements. 18.Patients who are breast feeding. 19.Patients who have a known hypersensitivity to the active ingredient or any of the excipients including lactose.
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E.5 End points |
E.5.1 | Primary end point(s) |
•PK parameters of nilotinib, i.e. AUC0-∞, Cmax, Cmin, tmax, t½, Vd/F, AUC0-τ and CL/F. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
at predefined timepoints as described in the study protocol |
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E.5.2 | Secondary end point(s) |
Safety and tolerability: measures such as incidence and severity of adverse event and abnormal blood laboratory tests. Activity: hematologic, cytogenetic, and molecular response. Mutational assessments of BCR-ABL by PCR analysis. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Evaluation of pharmacokinetics |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 16 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
France |
Germany |
Italy |
Netherlands |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |