E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult patients treated with a planned dose of nilotinib 300 mg BID (or at a reduced dose level of 400 mg QD if required from the perspective of tolerance) for a minimum of 2 calendar years for newly diagnosed BCR-ABL positive Chronic Myelogenous Leukemia in chronic phase and have achieved MR 4.5 (BCR-ABL ≤ 0.0032% IS) at any time point before being enrolled in the study |
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E.1.1.1 | Medical condition in easily understood language |
Adult patients with CML who have been treated with nilotinib (Tasigna) for at least two years and who have achieved a certain level of molecular response prior to study entry. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054352 |
E.1.2 | Term | Chronic phase chronic myeloid leukemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 determine the percentage of patients who are in Major Molecular Response (MMR) at 48 weeks after starting the treatment-free remission (TFR) phase (patients who required re-initiation of treatment will be considered as non-responders)
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E.2.2 | Secondary objectives of the trial |
1) To determine the percentage of patients who are in MR4.5 (BCR-ABL ≤ 0.0032% IS) at 48 weeks after starting the TFR phase(patients who required re-initiation of treatment will be considered as non-responders)
2) To determine the percentage of patients who are in MMR at 96, 144, 192, 264 weeks, and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase (patients who required re-initiation of treatment will be considered as non-responders)
3) To determine the percentage of patients who are in MR4.5 at 96, 144, 192, 264 weeks, and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase (patients who required re-initiation of treatment will be considered as non-responders)
4) To determine the percentage of patients in MMR at 48, 96, 144, 192, 264 weeks, and at the end of 6, 7, 8, 9 and 10 years after starting the TFR phase of nilotinib irrespective of whether or not patients required reinitiation of treatment
Additional objectives apply. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study have to meet all of the following criteria; additional inclusion criteria may apply as per protocol:
1) Male or female patients ≥18 years of age
2) Minimum of 2 calendar years of nilotinib treatment with at least the
last 12 months of
nilotininb treatment prior to pre-screening at the approved total daily
dose of 600 mg or at a reduced dose of 400 mg QD if required from the
perspective of tolerance for BCR-ABL positive CML in documented
chronic phase at the time of diagnosis
3) Evidence of typical BCR-ABL transcripts [b3a2 (e14a2) and/or b2a2
(e13a2)] at the time of CML-CP diagnosis i.e. prior to first start of TKI
treatment which are amenable to standardized RT-PCR quantification"
4) Patient in MR4.5 at prescreening at Novartis designated lab
5) ECOG performance status of 0-2
6) Adequate end organ function as defined by:
• Direct bilirubin ≤ 1.5 x ULN, except for i) patients with documented
Gilbert's syndrome
for whom any bilirubin value is allowed and ii) for patients with
asymptomatic
hyperbilirubinemia (liver transaminases and alkaline phosphatase within
normal range)
• SGOT(AST) and SGPT(ALT) ≤ 3 x ULN i.e. equivalent to ≤ Grade 1 NCICTCAE
v.4.03
• Serum lipase ≤ 2 x ULN i.e. equivalent to ≤ Grade 2 NCI-CTCAE v.4.03
• Alkaline phosphatase ≤ 2.5 x ULN
• Serum creatinine < 1.5 x ULN
7) Patients must have the following electrolyte values within normal
limits or corrected to be within normal limits with supplements prior to
first dose of study medication:
• Potassium (suggested keep to prevent issues with QT and/or rhythm
abnormalities)
• Magnesium (suggested keep to prevent issues with QT and/or rhythm
abnormalities)
• Total calcium (corrected for serum albumin)
8) Patients must have normal marrow function as defined:
• Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L
• Hemoglobin ≥ 9.0 g/dL
• Platelets ≥ 100 x 109/L
Additional inclusion criteria are defined in the protocol. |
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E.4 | Principal exclusion criteria |
Patients eligible for this study must not meet any of the following criteria:
1) Previous treatment with BCR-ABL inhibitors other than nilotinib for more than a total cumulative duration of 4 weeks
2) Previous treatment with alpha-interferon of any duration
3) Previous anticancer agents for CML other than nilotinib except for cytoreduction after CML diagnosis until up to 4 weeks after first dose of nilotinib
4) Known second chronic phase of CML after previous progression to AP/BC
5) Poorly controlled diabetes mellitus (defined as HbA1c > 9%)
6) Impaired cardiac function as defined in the protocol
7) History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis
8) Known presence of significant congenital or acquired bleeding disorder unrelated to cancer
9) History of another active malignancy within 5 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively
10) Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 4 weeks of Day 1
11) Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug.
12) Patients actively receiving therapy with herbal medicines that are strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. These herbal medicines may include Echinacea, (including E. purpurea, E. angustifolia and E. pallida), Piperine, Artemisinin, St. John’s Wort, and Ginkgo.
13) Patients who are currently receiving treatment with any medications
that have the potential to prolong the QT interval and the treatment
cannot be either safely discontinued or switched to a different
medication prior to starting study drug. (Please see
http://crediblemeds.org/everyone/composite-list-all-qtdrugs/ for a list
of agents that prolong the QT interval)
14) 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)
15) Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
16) Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during the study and for 14 days after the final dose of nilotinib. Highly effective contraception is defined in the protocol.
Additional exclusion criteria are defined in the protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
BCR-ABL ≤ 0.1% IS (MMR or MR3) at 48 weeks after starting the treatment-free remission (TFR) phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
48 weeks after starting the TFR phase |
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E.5.2 | Secondary end point(s) |
1) BCR-ABL ≤ 0.0032% IS (MR4.5) at 48 weeks after starting the
treatment-free remission (TFR) phase with no loss of MR4.5 and no reinitiation of nilotinib therapy in the first 48 weeks after starting the TFR phase.
2) BCR-ABL ≤ 0.1% IS (MMR) at 96, 144, 192, 264 weeks, and at the end
of 6, 7, 8, 9, and 10 years after starting the TFR phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 96, 144, 192, 264 weeks , and in the firsts 6, 7, 8, 9, and 10 years after starting the TFR phase.
3) BCR-ABL ≤ 0.0032% IS (MR4.5) at 96, 144, 192, 264 weeks, and at
the end of 6, 7, 8, 9, and 10 years after starting the TFR phase with no
loss of MR4.5 and no re-initiation of nilotinib therapy in the first 96, 144, 192, 264 weeks, and in the first 6, 7, 8, 9, and 10 years after starting the TFR phase.
4) BCR-ABL ≤ 0.1% IS (MMR) at 48, 96, 144, 192, 264 weeks, and at the
end of 6, 7, 8, 9 and 10 years after starting the TFR phase. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) at 48 weeks after starting the TFR phase.
2) - 4) at 96, 144, 192, 264 weeks, and at the end of 6, 7, 8, 9, and 10
years after starting the TFR. |
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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 | 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 | Yes |
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 | 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.8.3 |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 117 |
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 |
Argentina |
Colombia |
China |
Japan |
United Kingdom |
United States |
Austria |
Belgium |
Bulgaria |
Denmark |
France |
Germany |
Greece |
Ireland |
Italy |
Netherlands |
Poland |
Spain |
Sweden |
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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 | 6 |
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 | 12 |