E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The trial aims to evaluate the efficacy and quality of life of nilotinib 300mg BID in patients with chronic myleoid leukemia in chronic phase. |
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E.1.1.1 | Medical condition in easily understood language |
The trial evaluates the proportion of patients with deep molecular response MR4.5 (IS) after two years of treatment with nilotinib 300mg BID. |
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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 | 20.0 |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the proportion of patients who are in deep molecular response MR4.5 (IS) at 24 months of study treatment, measured in a standardized EUTOS MR4.5 laboratory. |
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E.2.2 | Secondary objectives of the trial |
To determine the proportion of patients who are in deep molecular response MR4 (IS) at 24 months of study treatment.
To determine the proportion of patients who are in MMR at 12 months of study treatment.
To determine the proportion of patients who are in CCyR at 6 months of study treatment.
To evaluate progression-free survival (PFS) and time to progression to AP/BC.
To evaluate quality of life of 300mg nilotinib BID therapy.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female patients at least 18 years of age
2. ECOG 0, 1, or 2.
3. Patients within 6 months of diagnosis of CML in chronic phase with cytogenetic confirmation of Ph+ [t(9;22)
translocation]; if the bone marrow sample is taken within 12 weeks of the start of study treatment but before the
patient consents, the bone marrow should not be repeated after the patient formally consents to the study.
4. 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.
5. Patients must be previously untreated for CML with the exception of 6 months treatment with hydroxyurea and a
maximum of 6 weeks treatment with imatinib
6. Adequate end organ function as defined by:
• Total bilirubin < 1.5 x ULN (upper limit of normal) except know Mb. Gilbert
• AST (SGOT), ALT (SGPT) < 3 x ULN or ≤ 5.0 x ULN if considered due to leukemia
• Creatinine < 1.5 x ULN
• Serum amylase and lipase ≤ 1.5 x ULN
• Alkaline phosphatase ≤ 2.5 x ULN unless considered tumor related.
7. Normal serum levels ≥ LLN (lower limit of normal) of potassium, magnesium, total calcium corrected for serum albumin
or phosphorus, or correctable to within normal limits with supplements, prior to the first dose of study medication
8. Ability to provide written informed consent prior to any study related screening procedures being performed.
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E.4 | Principal exclusion criteria |
1. Contraindication to excipients in study medication
2. Known impaired cardiac function, including any of the following:
• 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 bradycardia (<50 beats per minute)
• QTcF >450 msec (using the QTcF formula). If QTcF > 450 msec and electrolytes are not within normal ranges,
electrolytes should be corrected and the patient re tested for the QTc
• History of clinically documented myocardial infarction within 12 months prior to study entry
• History of unstable angina during the last 12 months
• Other clinical significant heart disease (congestive heart failure)
3. History of acute (within 1 year of starting study medication) or chronic pancreatitis
4. Severe and/or uncontrolled concurrent medical conditions that in the opinion of the investigator could cause
unacceptable safety risks or compromise compliance with the protocol (e.g., acute artherothrombotic events (such as
ischemic heart disease, acute peripheral arterial occlusive disease, symptomatic carotid stenosis/cerebrovascular
accident), uncontrolled diabetes mellitus, active or uncontrolled infections, uncontrolled severe hypertension, and
uncontrolled severe dyslipidemia, acute or chronic liver or severe renal disease.
5. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug
6. History of significant congenital or acquired bleeding disorder unrelated to cancer
7. Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers
(see http://medicine.iupui.edu/clinpharm/ddis/main-table/)
or medications that have the potential to prolong the QT interval
(see https://www.crediblemeds.org/pdftemp/pdf/CombinedList.pdf) which cannot be either discontinued or switched to
a different medication prior to starting study drug
8. Patients who have not recovered from prior surgery
9. Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential without a negative pregnancy test prior
to baseline and (d) 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).
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are
using highly effective methods of contraception during dosing and for 14 days after the final dose of nilotinib. Patients
using an oral hormonal contraception method should complete their monthly treatment course. Highly effective
contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
• Female sterilization (surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
• Male sterilization (at least 6 months prior to screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject.
• Combination of any two of the following (a+b or a+c, or b+c) listed below:
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 hormone 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/film/cream/vaginal suppository
In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
10. Patients with a history of another primary malignancy that is currently clinically significant or currently requires active
intervention with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ
treated curatively
11. Treatment with other investigational agents within 30 days of Day 1
12. Patients not able to understand and to comply with study instructions and requirements
13. Refusal to give informed consent
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable is the rate of MR4.5 at 24 months of study treatment measured in a standardized EUTOS MR4.5 laboratory. MR4.5 is defined as either (i) detectable disease ≤ 0.0032% BCR-ABLIS or (ii) undetectable disease in cDNA with 32 000 – 99 999 ABL1 transcripts or 77 000 – 239 999 GUSB transcripts. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
evaluation will take place for all patients after 24 months of study treatment |
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E.5.2 | Secondary end point(s) |
MR4 (IS)
- MR4 (IS) is defined in this study as either (i) detectable disease ≤0.01% BCR-ABLIS or (ii) undetectable disease in cDNA with 10 000 – 31 999 ABL1 transcripts or 24.000 – 76 999 GUSB transcripts.
- The rate of MR4 (IS) at 24 months of study treatment will be computed by dividing the number of patients who fit the definition of response at 24 months by the total number of patients in the analysis set.
MMR
- MMR is defined as a ≥3 log reduction from the standardized baseline or ≤ 0.1% BCR-ABLIS
- The rate of MMR at 12 months of study treatment will be computed by dividing the number of patients who fit the definition of response at 12 months by the total number of patients in the analysis set
CCyR
- Complete cytogenetic response is defined as 0% Ph+ metaphases
- Rate of CCyR at 6 months of study treatment will be calculated by dividing the number of patients who fit the definition of response at 6 month by the total number of Ph+ patients in the analysis set
Outcome
- Time to progression to AP/BC is defined as the time from the date of start of study treatment to the date of earliest transformation to AP/BC, or CML-related death. Rates of progression at various time points will also be provided.
- Progression-free survival is defined as the time from the date of start of study treatment to the date of event defined as the first documented disease progression to AP/BC or the date of death from any cause, whichever is earlier.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
evaluation will take place for all patients after 24 months of study treatment |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | 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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 107 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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 | |
E.8.9.1 | In the Member State concerned days | |