A clinical research study evaluating the possibility to stop the drug nilotinib (Tasigna) in chronic myeloid leukemia (CML) patients who have very small amount of leukemia cells remaining after nilotinib (Tasigna) treatment.

• Register: EUCTR
• Last refreshed on: 30 June 2019
• Main ID: EUCTR2012-003186-18-GB
• Date of registration: 12/04/2013
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: A clinical research study evaluating the possibility to stop the drug nilotinib (Tasigna) in chronic myeloid leukemia (CML) patients who have very small amount of leukemia cells remaining after nilotinib (Tasigna) treatment.
• Scientific title: A phase II, single arm, open label study of treatment-free remission in Chronic Myeloid Leukemia (CML) chronic phase (CP) patients after achieving sustained MR4.5 on nilotinib - ENESTop
• Date of first enrolment: 24/06/2013
• Target sample size: 163
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-003186-18
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Argentina, Australia, Belgium, Brazil, Canada, France, Germany, Greece, Israel, Japan, Korea, Republic of, Mexico, Poland, Russian Federation, Saudi Arabia, Singapore, Spain, Tunisia, United Kingdom, United States

Contacts

• Name: Medical Information Services
• Affiliation: Novartis Pharmaceuticals UK Ltd

• Name: Medical Information Services
• Affiliation: Novartis Pharmaceuticals UK Ltd

Key inclusion & exclusion criteria

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

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 123
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 40

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, must have a negative
serum pregnancy test before initiation of study treatment and must also use highly unless they are using effective methods of contraception during dosing while enrolled in the study


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Ph+ chronic myeloid leukemia (CML)
MedDRA version: 20.0 Level: LLT Classification code 10054352 Term: Chronic phase chronic myeloid leukemia System Organ Class: 100000004864

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Trade Name: Tasigna
Product Name: nilotinib
Product Code: AMN107
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: NILOTINIB
CAS Number: 641571-10-0
Current Sponsor code: AMN107
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-

Trade Name: Tasigna
Product Name: nilotinib
Product Code: AMN107
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: NILOTINIB
CAS Number: 641571-10-0
Current Sponsor code: AMN107
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Trade Name: Tasigna
Product Name: nilotinib
Product Code: AMN107
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: NILOTINIB
CAS Number: 641571-10-0
Current Sponsor code: AMN107
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-

Trade Name: Tasigna
Product Name: nilotinib
Product Code: AMN107
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: NILOTINIB
CAS Number: 641571-10-0
Current Sponsor code: AMN107
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Trade Name: Tasigna
Product Name: nilotinib
Product Code: AMN107
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: NILOTINIB
CAS Number: 641571-10-0

Primary Outcome(s)

Main Objective: 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.

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.

Secondary Objective: 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.

Timepoint(s) of evaluation of this end point: Within the first 48 weeks following cessation of treatment.

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: as indicated in the protocol

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.

Secondary ID(s)

CAMN107A2408

2012-003186-18-ES

Source(s) of Monetary Support

Novartis Pharma Services AG

Ethics review

Status: Approved
Approval date:
Contact: