The main purpose of this study is to determine the rate of treatment-free molecular remission (MMR=MR3.0) after 48 weeks following start of the TFR phase. The study further seeks to provide evidence that suspending nilotinib therapy in these…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To determine the percentage of patients who are in MMR
(BCR-ABL * 0.1% IS (MR3)) at 48 weeks after starting the Treatment-Free
Remission (TFR) phase (patients who required re-initiation of treatment will be
considered as non-responders)
Secondary outcome
To evaluate the proportion of patients in TFR within 24, 36, and 48 monhs after
nilotinib cessation.
To estimate progression free survival after nilotinib cessation
To estimate treatment free survival.
Background summary
Stop imatinib study (STIM) (Mahon et al 2010) investigated feasibility of
imatinib
suspension in a highly selected group of patients who achieved and maintained
complete molecular response (CMR) defined as undetectable BCR-ABL levels with
high sample sensitivity (10-5 or greater) for a minimum of 2 years. With a
median
follow up of 34 months (Mahon et al 2011), 39% of patients have successfully
remained in treatment-free remission. This provided the first evidence that
achieving and maintaining deep molecular responses can lead to successful
therapy suspension. In terms of regaining molecular response, 61 patients had a
molecular recurrence and 56 regained undetectable BCR-ABL transcript level
after
median of 4 months on imatinib (range 0-21 months). Five patients did not
return to
undetectable transcript level: four remained treatment-free with detectable
transcript (range 0.05% to 0.3%) and one patient was switched to dasatinib due
to
loss of CCyR (Mahon et al 2011). No loss of hematological response or
progression to advanced phase was noted after stopping imatinib.
Based on results of ENESTnd [CAMN107A2303], nilotinib enables a higher
proportion of newly diagnosed patients to achieve deep levels (MR4.0 (molecular
response 4.0 log reduction from standardized baseline) or MR4.5) of MR vs.
imatinib and potentially to be eligible for treatment suspension.
The study intends to generate data on the safety, feasibility and success of
TFR
phase in a rigorously controlled manner.
Study objective
The main purpose of this study is to determine the rate of treatment-free
molecular remission (MMR=MR3.0) after 48 weeks following start of the TFR
phase.
The study further seeks to provide evidence that suspending nilotinib therapy
in these eligible patients does not cause short- or long-term harm to them.
Study design
This is a single-arm, open label study. This study has 2 main phases: nilotinib
consolidation phase (48 weeks), and nilotinib treatment-free remission (TFR)
phase (week 48 * week 240).
Intervention
Stop nilotinib treatment
Study burden and risks
The biggest risk in this study is recurrence of CML, but from previous studies,
it is known that with reinitiation of therapy, complete remission can be
induced quickly again.
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
Male or female patients *18 years of age
ECOG performance status of 0-2
Patient with diagnosis of BCR-ABL positive CML
Patient has received minimum of 3 years of tyrosine kinase inhibitor treatment (first with imantinib and then switched to nilotinib) since initial diagnosis
Minimum of 2 calendar years of nilotinib treatment before study entry
Patient has achieved MR4.5 (local laboratory assessment) during nilotinib treatment, and determined by a Novartis designated central PCR lab assessment at screening.
Adequate end organ function as defined by:
* Direct bilirubin * 1.5 x ULN
* SGOT(AST) and SGPT(ALT) * 3 x ULN
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
Patients must have the following electrolyte values above LLN limits or corrected to be within normal limits with supplements prior to
first dose of study medication:
* Potassium
* Magnesium
* Total calcium (corrected for serum albumin)
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
Exclusion criteria
Prior AP, BC or allo-transplant
Patient has documented MR4.5 at the time when switched from imatinib to nilotinib
Patients with known atypical transcript
Mutation(s) (T351I, 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)
Dose reductions due to neutropenia or thrombocytopenia in the past 6 months
Patient ever attempted to permanently discontinue imatinib or nilotinib treatment
Known impaired cardiac function
History of acute pancreatitis
Known presence of a significant congenital or acquired bleeding disorder unrelated to
cancer
History of other active malignancy within 5 years prior to study entry
Treatment with other investigational agents (defined as not used in accordance with the
approved indication) within 4 weeks of Day 1
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-003186-18-NL |
| ClinicalTrials.gov | NCT01698905 |
| CCMO | NL44493.029.13 |