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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT01698905




Registration number
NCT01698905
Ethics application status
Date submitted
1/10/2012
Date registered
3/10/2012

Titles & IDs
Public title
Treatment-free Remission After Achieving Sustained MR4.5 on Nilotinib (ENESTop)
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
Secondary ID [1] 0 0
2012-003186-18
Secondary ID [2] 0 0
CAMN107A2408
Universal Trial Number (UTN)
Trial acronym
ENESTop
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Myeloid Leukemia 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - nilotinib

Experimental: Nilotinib - Patients with minimum 3 years of tyrosine kinase inhibitor treatment (first with imatinib and then switched to nilotinib) since initial diagnosis, at least 2 years of nilotinib treatment prior to study entry and who achieved MR4.5 (local laboratory assessment) during nilotinib treatment, and determined by a Novartis designated central PCR lab assessment at screening


Treatment: Drugs: nilotinib
Nilotinib was dosed by weight or body surface area.

Nilotinib 300 mg BID or 400 mg BID was be administered orally at approximately 12 hour intervals, and must not have been taken with food. The capsules were to be swallowed whole with water.

No food should have been consumed for at least 2 hours before the dose was taken and no additional food should have been consumed for at least one hour after the dose was taken. Patients were also allowed to enter this study on the same dose they were taking prior to study entry. Patients who required permanent dose reduction from their original starting dose were to be allowed to enter this study on the same dose only if the patient maintained this dose for a minimum of 6 months prior to study entry.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Percentage of Patients in Treatment Free Remission (TFR) Within 48 Weeks
Timepoint [1] 0 0
First 48 weeks following nilotinib cessation.
Secondary outcome [1] 0 0
Percentage of Patients in Treatment Free Remission (TFR) Within 96, 144, 192, 264 Weeks and Within 6,7,8,9 and 10 Years
Timepoint [1] 0 0
96, 144, 192, 264 weeks and within 6,7,8,9 and 10 years following nilotinib cessation
Secondary outcome [2] 0 0
Progression Free Survival (PFS) to Accelerated Phase/Blast Crisis (AP/BC) or Death
Timepoint [2] 0 0
nilotinib cessation up to approximately 580 weeks
Secondary outcome [3] 0 0
Treatment Free Survival (TFS)
Timepoint [3] 0 0
nilotinib cessation up to approximately 580 weeks
Secondary outcome [4] 0 0
Overall Survival (OS)
Timepoint [4] 0 0
nilotinib cessation up to approximately 580 weeks
Secondary outcome [5] 0 0
Change in BCR-ABL (Oncoprotein Product of BCR-ABL Fusion Gene) Transcripts After Re-start of Nilotinib Therapy
Timepoint [5] 0 0
re-start of nilotinib up to approximately 48 weeks
Secondary outcome [6] 0 0
Percentage of Patients With Stable MMR in Nilotinib Re-initiation Phase
Timepoint [6] 0 0
start of nilotinib in re-initiation phase up to approximately 432 weeks
Secondary outcome [7] 0 0
Percentage of Patients With Stable MR4 in Nilotinib Re-initiation Phase
Timepoint [7] 0 0
start of nilotinib in re-initiation phase up to approximately 432 weeks
Secondary outcome [8] 0 0
Percentage of Patients With Stable MR4.5 in Nilotinib Re-initiation Phase
Timepoint [8] 0 0
start of nilotinib in re-initiation phase up to approximately 432 weeks

Eligibility
Key inclusion 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 (> 4 weeks) 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 by:

* Direct bilirubin = 1.5 x ULN except for i) patient 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 (upper limit of normal)
* Serum lipase = 2 x ULN
* Alkaline phosphatase = 2.5 x ULN
* Serum creatinine < 1.5 x ULN
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:

* Potassium
* Magnesium
* Total calcium (corrected for serum albumin)
9. Patients must have normal marrow function as defined below:

* Absolute Neutrophil Count (ANC) = 1.5 x 109/L
* Platelets = 100 x 109/L
* Hemoglobin = 9.0 g/dL
10. Written informed consent obtained prior to any screening procedures
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion 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
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 including any one of the following:

* Inability to determine the QT interval on ECG
* Complete left bundle branch block
* 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
* QTcF > 480 msec
* History or clinical signs of myocardial infarction within 1 year prior to study entry
* History of unstable angina within 1 year prior to study entry
* Other clinically significant heart disease (e.g. uncontrolled congestive heart failure or uncontrolled hypertension)
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. See Appendix 14.1 for a list of these medications. This list may not be comprehensive.
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. These herbal medicines may include Echinacea, (including E. purpurea, E. angustifolia and E. pallida), Piperine, Artemisinin, St. John's Wort, and Ginkgo.
16. 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 study entry. (Please see www.azcert.org/medical-pros/drug-lists/printable-drug-list.cfm for a list of agents that prolong the QT interval.)
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 effective methods of contraception while enrolled in the study. The use of highly effective contraception should continue for at least 14 days after the last dose of study treatment or until the last day of TFR/TFR-2, or for the duration of a monthly cycle of oral contraception, whichever is longer. Acceptable forms of highly effective contraception methods include:

* Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
* Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total 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). The vasectomized male partner should be the sole partner for that subject Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception, women should be stable on the same pill for a minimum of 3 months before taking study treatment. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks prior to enrolling. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential. If a study patient becomes pregnant or is suspected of being pregnant during the study or within 30 days as part of safety evaluations after the final dose of nilotinib, the Study Doctor needs to be informed immediately and any ongoing study treatment with nilotinib has to be stopped immediately.

Study design
Purpose of the study
Treatment
Allocation to intervention
NA
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
20/12/2012
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
19/01/2025
Actual
Sample size
Target
Accrual to date
Final
163
Recruitment in Australia
Recruitment state(s)
SA,VIC
Recruitment hospital [1] 0 0
Novartis Investigative Site - Adelaide
Recruitment hospital [2] 0 0
Novartis Investigative Site - Box Hill
Recruitment postcode(s) [1] 0 0
5000 - Adelaide
Recruitment postcode(s) [2] 0 0
3128 - Box Hill
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
California
Country [2] 0 0
United States of America
State/province [2] 0 0
Indiana
Country [3] 0 0
United States of America
State/province [3] 0 0
Maryland
Country [4] 0 0
United States of America
State/province [4] 0 0
Texas
Country [5] 0 0
United States of America
State/province [5] 0 0
Washington
Country [6] 0 0
Argentina
State/province [6] 0 0
Buenos Aires
Country [7] 0 0
Belgium
State/province [7] 0 0
Antwerp
Country [8] 0 0
Brazil
State/province [8] 0 0
GO
Country [9] 0 0
Brazil
State/province [9] 0 0
MG
Country [10] 0 0
Brazil
State/province [10] 0 0
RJ
Country [11] 0 0
Brazil
State/province [11] 0 0
RS
Country [12] 0 0
Brazil
State/province [12] 0 0
SP
Country [13] 0 0
Canada
State/province [13] 0 0
Ontario
Country [14] 0 0
Canada
State/province [14] 0 0
Quebec
Country [15] 0 0
France
State/province [15] 0 0
Bordeaux
Country [16] 0 0
France
State/province [16] 0 0
Grenoble
Country [17] 0 0
France
State/province [17] 0 0
Lyon
Country [18] 0 0
France
State/province [18] 0 0
Strasbourg cedex
Country [19] 0 0
France
State/province [19] 0 0
Vandoeuvre les Nancy
Country [20] 0 0
Germany
State/province [20] 0 0
Baden Wuerttemberg
Country [21] 0 0
Germany
State/province [21] 0 0
Berlin
Country [22] 0 0
Germany
State/province [22] 0 0
Heilbronn
Country [23] 0 0
Germany
State/province [23] 0 0
Potsdam
Country [24] 0 0
Germany
State/province [24] 0 0
Ulm
Country [25] 0 0
Greece
State/province [25] 0 0
GR
Country [26] 0 0
Greece
State/province [26] 0 0
Athens
Country [27] 0 0
Israel
State/province [27] 0 0
Haifa
Country [28] 0 0
Israel
State/province [28] 0 0
Petach Tikva
Country [29] 0 0
Israel
State/province [29] 0 0
Ramat Gan
Country [30] 0 0
Japan
State/province [30] 0 0
Aichi
Country [31] 0 0
Japan
State/province [31] 0 0
Chiba
Country [32] 0 0
Japan
State/province [32] 0 0
Fukuoka
Country [33] 0 0
Japan
State/province [33] 0 0
Akita
Country [34] 0 0
Japan
State/province [34] 0 0
Aomori
Country [35] 0 0
Korea, Republic of
State/province [35] 0 0
Seocho Gu
Country [36] 0 0
Mexico
State/province [36] 0 0
Nuevo Leon
Country [37] 0 0
Poland
State/province [37] 0 0
Malopolskie
Country [38] 0 0
Poland
State/province [38] 0 0
Gdansk
Country [39] 0 0
Poland
State/province [39] 0 0
Warszawa
Country [40] 0 0
Russian Federation
State/province [40] 0 0
Moscow
Country [41] 0 0
Russian Federation
State/province [41] 0 0
Saint Petersburg
Country [42] 0 0
Russian Federation
State/province [42] 0 0
St Petersburg
Country [43] 0 0
Singapore
State/province [43] 0 0
Singapore
Country [44] 0 0
Spain
State/province [44] 0 0
Andalucia
Country [45] 0 0
Spain
State/province [45] 0 0
Cantabria
Country [46] 0 0
Spain
State/province [46] 0 0
Catalunya
Country [47] 0 0
Spain
State/province [47] 0 0
Comunidad Valenciana
Country [48] 0 0
Spain
State/province [48] 0 0
Santa Cruz De Tenerife
Country [49] 0 0
Spain
State/province [49] 0 0
Madrid
Country [50] 0 0
United Kingdom
State/province [50] 0 0
Liverpool
Country [51] 0 0
United Kingdom
State/province [51] 0 0
Nottingham

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Novartis Pharmaceuticals
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Novartis Pharmaceuticals
Address 0 0
Novartis Pharmaceuticals
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com
When will data be available (start and end dates)?
Available to whom?
Available for what types of analyses?
How or where can data be obtained?


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results are available at https://clinicaltrials.gov/study/NCT01698905