| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia in chronic phase (CML-CP) |
|
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To establish the Complete Cytogenetic Response Rate at 6 months. |
|
| E.2.2 | Secondary objectives of the trial |
1. To establish the Complete Cytogenetic Response Rates (CCyR) at 3, 9, 12, 18 and 24 months
2. To establish Molecular Response Rates (MMR/CMR) at 3, 6, 9, 12,18 and 24 months
3. To establish the safety of a twice daily dose of Nilotinib 300mg
4. To correlate pharmacokinetic data with response rates and toxicity
5. To correlate Bcr-Abl results using the GeneXpert system with international standardized
QPCR
6. To estimate the prevalence of Bcr-Abl mutations prior to and during therapy with nilotinib |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Male or female patients ≥ 18 years of age
• ECOG performance status 0, 1, or 2
• Patients with CML-CP within 6 months of diagnosis (date of initial diagnosis is the date of first cytogenetic analysis). Standard conventional cytogenetic analysis must be done on bone marrow. FISH cannot be used.
• Diagnosis of chronic myelogenous leukemia in chronic phase with
cytogenetic confirmation of Philadelphia chromosome of (9;22)
translocations in more than one metaphase to prove clonality (where
possible a review of up to 20 metaphases is desirable to provide a
more accurate assessment of baseline Ph+ chromosome positivity and
exclude cytogenetic clonal evolution). Evaluation of metaphases with
chromosome banding analysis on peripheral blood will be allowed to
confirm the presence of the Philadelphia chromosome in rare cases
where the peripheral blood yields sufficient metaphases when the
marrow does not. Cytogenetic confirmation is required as complete
cytogenetic response is the primary endpoint of this study (i.e.
confirmation of Bcr-Abl by FISH alone is not sufficient)
• Documented chronic phase CML will meet all the criteria defined by:
1. <15% blasts in peripheral blood and bone marrow
2. <30% blasts plus promyelocytes in peripheral blood and bone marrow,
3. <20% basophils in the peripheral blood,
4. ≥100 x 109/L (≥100,000/mm3) platelets
5. No evidence of extramedullary leukemic involvement, with the exception of
hepatosplenomegaly.
• Adequate end organ function as defined by:
1. total bilirubin <1.5xULN
2. AST and ALT <2.5xULN
3. estimated GFR of ≥ 30 ml/min
4. Serum amylase and lipase ≤1.5xULN
5. Aklaline phosphatase ≤ 2.5 xULN unless considered tumor related
• Female patients of childbearing potential must have a negative serum pregnancy test within 7 days before initiation of study drug
• Patients must have the following laboratory values (≥(lower limit of normal) or corrected to within normal limits with supplements prior to the first dose of study medication:-
1. Potassium ≥LLN
2. Magnesium ≥ LLN
3. Phosphorous ≥ LLN
4. Total calcium, (corrected for serum albumin) ≥ LLN
• Ability to provide written informed consent prior to any study related screening procedures being performed.
• Signed written informed consent to participate in the study by subject |
|
| E.4 | Principal exclusion criteria |
Patients who are considered Ph- because they do not have a confirmed cytogenetic diagnosis of Philadelphia Chromosome with (9,22) translocation
• Previously documented T315I mutations
• Any previous exposure to dasatinib or any other medical treatment for CML. Exceptions are imatinib which will be allowed for up to 2 weeks and Hydroxyurea and Anagrelide which will be allowed for up to 4 weeks.
Impaired cardiac function including any one of the following:-
*LVEF<45% or below the institutional lower limit of the normal range (whichever is higher) as determined by echocardiogram
*Inability to determine the QT interval on ECG
*Complete left bundle branch block
*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).
*QTc>450 msec on a baseline ECG (using the QTcF formula). If QTcF>450msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-scanned for QTc.
*History of clinically documented myocardial infarction within past 12 months
*History of unstable angina (during the last 12 months)
*Other clinically significant heart disease (e.g. congestive heart failure or uncontrolled hypertension).
• Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or uncontrolled infection).
• History of significant congenital or acquired bleeding disorder unrelated to cancer.
• Major surgery within 4weeks prior to day-1 of study or who have not recovered from prior surgery.
• Treatment with other investigational agents within 30 days of Day-1.
• History of non-compliance to medical regimens or inability to grant consent
• Patients with other primary malignancy except if the other primary malignancy is neither currently clinically significant or requiring active intervention
• Patients actively receiving therapy with strong CYP3A4 inhibitors (e.g. erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. See link for complete list of these medications: http://medicine.iupui.edu/flockhart/table.htm. The Principal Investigator must be contacted if a patient needs to be started on any of these drugs during study treatment.
• Patients actively receiving therapy with strong CYP3A4 inducers, (e.g. Dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbitol, St. John’s Wort) and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. See link for complete list of these medications: http://medicine.iupui.edu.flockhart/table.htm. The Principal Investigator must be contacted if a patient needs to be started on any of these drugs during study treatment.
• 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, malabsorption syndrome, small bowel resection, or gastric bypass surgery).
• History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis.
• Acute or chronic liver, pancreatic or severe renal disease considered unrelated to CML
• Patients who are currently receiving treatment with any medications that have the potential to prolong QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. (Please see http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm for a comprehensive list of agents that prolong the QT interval.)
• Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential without a negative pregnancy test prior to baseline and (d) male or female of childbearing potential unwilling to use contraceptive precautions throughout the trial (post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential).
• Subjects who are legally detained in an official institute |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Complete Cytogenetic Response at 6 months. |
|
| E.5.2 | Secondary end point(s) |
| Molecular Response (MMR/CMR) and Complete Cytogenetic Response (CyCR) at 3, 6, 9, 12, 18, and 24 months. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | No |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 2 |
| 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 |
| Germany |
| Israel |
| United Kingdom |
| United States |
|
| 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
|
| Patients will be followed in this study for 2 years during study treatment as per the Visit Evaluation Schedule. All patients who completed the study treatment will be followed for survival every 6 months until 5 years after the patient´s start of the study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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