| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Ph+ chronic myeloid leukemia (CML) |
|
| E.1.1.1 | Medical condition in easily understood language |
| a specific form of leukemia, called chronic myeloid leukemia |
|
| 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) |
|
| 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 |
| The purpose of this study is to determine the rate of successful treatment-free remission (TFR) within the first 48 weeks following cessation of treatment in patients who achieved and maintained a molecular response (MR) 4.5 on nilotinib after a switch from imatinib. TFR phase is often referred to as discontinuation phase in other studies. |
|
| E.2.2 | Secondary objectives of the trial |
1) To evaluate the proportion of patients in TFR within 96, 144, 192, 264
weeks, and within the end of years 6, 7, 8, 9 and 10 following nilotinib
cessation
2) To estimate progression-free survival (PFS) following nilotinib
cessation
3) To estimate treatment-free survival (TFS)
4) To estimate overall survival (OS)
5) To characterize the kinetics of BCRABL transcript after re-start of
nilotinib therapy
6) To determine the percentage of patients who are in stable MMR after
achievement of that response in the nilotinib re-initiation phase for 48
weeks, 96 weeks, 144 weeks, 192 weeks, 240 weeks, 288 weeks, 336
weeks, 384 weeks and 432 weeks, based on availability of appropriate
data.
7) To determine the percentage of patients who are in stable MR4 after
achievement of that response in the nilotinib re-initiation phase for 48
weeks, 96 weeks, 144 weeks, 192 weeks, 240 weeks, 288 weeks, 336
weeks, 384 weeks and 432 weeks, based on availability of appropriate
data. |
|
| 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:
1. Male or female patients ≥ 18 years of age
2. ECOG Performance Status of 0, 1, or 2
3. Patient with diagnosis of BCR-ABL positive CML CP
4. Patient has received a minimum of 3 years of tyrosine kinase inhibitor treatment (first with imatinib and then switched to nilotinib) since initial diagnosis
5. Patient has at least 2 years of nilotinib treatment prior to study entry.
6. Patient has achieved MR4.5 (local laboratory assessment) during nilotinib treatment, and determined by a Novartis designated central PCR lab assessment at screening
7. Adequate end organ function as defined in the protocol
8. Patients must have the following electrolyte values ≥ LLN (lower limit of normal) limits or corrected to within normal limits with supplements prior to the first dose of study medication as defined in the protocol.
9. Patients must have normal marrow function as defined in the protocol
10. Written informed consent obtained prior to any screening procedures
|
|
| E.4 | Principal exclusion criteria |
Patients eligible for this study must not meet any of the following criteria:
1. Prior AP, BC or allo-transplant
2. Patient has documented MR4.5 at the time when switched from imatinib to nilotinib
3. Patients with known atypical transcript. An atypical transcript is defined by the presence of any transcript in the absence of the major transcripts b3a2 (e14a2) and b2a2 (e13a2) or p210 protein.
4. CML treatment resistant mutation(s) (T315I, E255K/V, Y253H,
F359C/V) detected if a testing was done in the past (there is no requirement to perform mutation testing at study entry if it was not done in the past)
5. Dose reductions due to neutropenia or thrombocytopenia in the past 6 months
6. Patient ever attempted to permanently discontinue imatinib or nilotinib treatment
7. Known impaired cardiac function as defined in the protocol
8. Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. uncontrolled diabetes (defined as HbA1c > 9%), uncontrolled infection)
9. History of acute pancreatitis within 1 year prior to study entry or past medical history of chronic pancreatitis
10. Known presence of a significant congenital or acquired bleeding disorder unrelated to cancer
11. History of other active malignancy within 5 years prior to study entry with the exception of previous or concomitant basal cell skin cancer, previous cervical carcinoma in situ treated curatively
12. Patients who have not recovered from prior surgery
13. Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 4 weeks of Day 1
14. 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 study entry.
15. 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 study entry.
16. Patients who are currently receiving treatment with any medications that are known to prolong the QT interval and the treatment cannot be either safely discontinued or switched to a different medication prior to study entry.
17. 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)
18. 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.
19. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment and must also
use highly unless they are using effective methods of contraception
during dosing while enrolled in the study.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| No documented confirmed loss of MR4, no documented loss of MMR and no re-starting of nilotinib therapy in the first 48 weeks following nilotinib cessation. Confirmed loss of MR4 is two consecutive BCR-ABL > 0.01% International Standard. Loss of MMR does not require confirmation. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Within the first 48 weeks following cessation of treatment. |
|
| E.5.2 | Secondary end point(s) |
1) No documented confirmed loss of MR4, no documented loss of MMR and no re-starting of nilotinib therapy in the first 96, 144, 192, 264weeks, and within the end of years 6, 7, 8, 9 and 10 following nilotinib cessation. Confirmed loss of MR4 is two consecutive BCR-ABL >0.01% IS. Loss of MMR does not require any confirmation.
2) Progression to AP/BC or death where the "failure" event is the earliest occurrence of the following event: progression to AP/BC or death from any cause.
3) TFS is defined as the lack of any of the following events: loss of MMR, confirmed loss of MR4, restart of nilotinib treatment, progression to AP/BC or death from any cause.
4) OS is defined as the time from the date of cessation of nilotinib therapy to the date of death from any cause.
5) BCR-ABL transcript changes within 48 weeks after re-start of nilotinib therapy.
6) BCR-ABL ≤ 0.1% IS (MMR) at 48 weeks, 96 weeks or subsequent time points since first achievement of MR4.5 during the nilotinib reinitiation phase.
7) BCR-ABL ≤ 0.01% IS (MR4) at 48 weeks, 96 weeks or subsequent time points since first achievement of MR4.5 during the nilotinib reinitiation phase. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| as indicated in the protocol |
|
| 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 | 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 | 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.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 32 |
| 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 |
| Singapore |
| Australia |
| Brazil |
| Canada |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Russian Federation |
| United Kingdom |
| United States |
| Belgium |
| France |
| Germany |
| Greece |
| Poland |
| Spain |
|
| 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
|
| End of the study (EOS) occurs 528 weeks after the last patient enters the nilotinib treatment-free remission (TFR) phase. At this point all patients will have completed the TFR phase, or completed nilotinib treatment, or discontinued the study early |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 12 |
| 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 |
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