Phase II Explorative Study of Intermittent Imatinib (IM) Treatment (INTERIM) in Elderly Patients With Ph+ Chronic Myeloid Leukemia (CML) Who Achieved a Stable Complete Cytogenetic Response (CCgR) With Standard IM Therapy
Objective: The aim of the study is to investigate if the complete cytogenetic response
(CCgR) that has been achieved with standard (daily administration) Imatinib (IM) therapy
can be maintained with the same dose of IM given intermittently (INTERIM). For the purposes
of this study, the term "standard IM therapy" means the daily administration of IM at any
dose between 300 and 800mg, whereas, "intermittent IM treatment" (INTERIM), is defined as
the same daily dose of IM given one month on/one month off .
The primary objective of the study is to evaluate the proportion of patients who remain in
CCgR with INTERIM given for one year.
Study design: This study is an open-label, multicenter, Phase II study of INTERIM for the
maintenance of CCgR.
Study Population: Elderly patients (at least 65 years) with Ph+ CML and with stable CCgR
after at least 2 years of standard (daily administration ) IM therapy
Treatment Plan STUDY DRUG: Imatinib is registered as Glivec by Novartis Pharma Italy for
treatment of patients with Ph+ CML in any phase (CP and AP/BP).
DOSE AND SCHEDULE: Imatinib (Glivec) is given at the same daily dose that was given at the
time of the enrollment by the following intermittent schedule:
- 1 week on / 1 week off for the 1st month(weeks 1-4)
- 2 weeks on / 2 weeks off for the 2nd and the 3rd month(weeks 5-12)
- 1 month on / 1 month off from the 4th month thereafter(weeks 13 on)
TREATMENT DURATION: The study has a duration of 12 months. After 12 months of intermittent
dose of IM (INTERIM) the patients who are in continuous CCgR are advised to continue study
treatment dose (INTERIM) but can go back to pre-study daily dose. Follow up is required
indefinitely for all patients.
Efficacy The primary efficacy variable of intermittent dose of IM (INTERIM) is measured by
the proportion of patients who maintain a stable CCgR over the whole study period (12
months). For the purposes of this study the monitoring of the cytogenetic response (CgR)
status will be evaluated by Fluorescence-in-situ-Hybridization (FISH) of interphase
peripheral blood cells (molecular cytogenetic analysis)
OFF TREATMENT EVENTS
Patients go off the study in case of failure:
- Loss of CCgR
- Loss of CHR
- Progression to AP/BP or in case of:
- Patient's refusal
- Documentation of serious adverse events (SAE)
- Protocol violation
OFF-TREATMENT THERAPEUTIC RECOMMENDATIONS
- In case of Loss of CCgR
- intermittent dose of IM (INTERIM) has to be STOPPED
- evaluation of additional cytogenetic abnormalities (ACA) by conventional
(morphologic) cytogenetics has to be performed
- mutational analysis of BCR-ABL transcript has to be checked
- and pre-study IM standard therapy (daily dose administration) has to be RESUMED
- In case of Loss of CHR or Disease Progression to AP/BP
- intermittent dose of IM (INTERIM) has to be STOPPED
- and it is recommended to move to investigational available treatments, based on
cytogenetic and molecular data
- In case of SAE: it is recommended to discontinue IM forever
- In case of Refusal or Protocol Violation: it is recommended to go back to pre-study IM
Concomitant Treatments All patients who are enrolled in this study have already been treated
with IM for a minimum of 2 years. Therefore, it is expected that the problems concerning
concomitant treatments have already been considered and that the investigators and the
patients are familiar with them. However, it is wise to remind that IM is a competitive
inhibitor of CYP2D6 and CYP3A4/5. Interactions are possible when IM is administered with
drugs whose metabolism is dependent on or which a1ter levels of these P450 cytochrome
isoenzymes. When drugs classified as 'substrates' are co-administered with IM, there is the
potential for higher concentrations of the 'substrate'. When IM is co-administered with
compounds classified as 'inhibitors', increased plasma concentrations of Imatinib is the
potential outcome. Particular attention is drawn to the potential interaction between IM and
acetaminophen, anticoagulants (especially warfarin) and anticonvulsants.
Visit Schedule, Assessments and Follow-up
- Clinical evaluation and physical examination, including height, weight, vital signs and
other relevant findings will be assessed at the time of enrollment (baseline) and every
3 months during the study (12 months).
- Cardiac function assessment will be performed by echocardiography at baseline, and at
the end of the study.
- Blood count including Hb, Plt count, WBC and differential will be performed at baseline
and will be monitored every 3 months during the study.
- Serum chemistry, including BUN, creatinine, AST, ALT, ALP, bilirubin, Ca, P, K and Mg,
total protein concentration and electrophoretic profile, IgG, IgA, IgM concentration
will be performed at baseline and every 3 months during the study.
- The cytogenetic response (CgR) status has to be evaluated at baseline and every 3
months during the study
- At baseline (BL) the cytogenetic response (CgR) status must be evaluated by
conventional (morphologic) AND by molecular cytogenetics (FISH) analysis.
- The monitoring of the cytogenetic response (CgR) status (months 3, 6, 9 and 12)
will be evaluated only by Fluorescence-in-situ-Hybridization (FISH) of interphase
peripheral blood cells (see section 11.1 page 19). FISH has the potential
advantage of i) evaluating many more cells and of using peripheral blood instead
of marrow, ii) reducing missing information by conventional morphologic evaluation
of marrow cells metaphases, iii) improving the compliance of patients for
- If FISH documents a variation of the baseline value of more than 1%, check again
the CgR by a second FISH analysis after 1 months
- If the second FISH analysis confirms a variation of the baseline value of more
than 1%, conventional cytogenetics by evaluation of marrow cells metaphases has to
be performed to confirm the Cytogenetic Response Loss (CgR loss) and to check for
additional cytogenetic abnormalities (ACA)
- Quantitative molecular assessment of BCR-ABL transcript by RQ-PCR on peripheral blood
sample is due at baseline and every 3 months during the study.
- Mutational analysis has to be performed in case of loss of CCgR on marrow cells.
- Follow up is required indefinitely for all patients by standard hematologic,
cytogenetic and molecular criteria.
Sample Size This study has been designed according to the optimal Simon's two stage
procedure, based on data of the annual rates of treatment failure reported in 454 patients
receiving IM in the multicenter, open-label, phase III randomized international study IRIS.
The optimal two-stage design to test the null hypothesis that P<= 0.850 versus the
alternative that P>= 0.950 has an expected sample size of 33.7 and a probability of early
termination of 0.602. If the INTERIM regimen is not effective (in the sense of maintaining a
complete cytogenetic response less than 0.85), there is a 0.049 probability of concluding
that it is (the target for this value was 0.050). If the INTERIM regimen is effective (in
the sense of maintaining a complete cytogenetic response more than 0.85), there is a 0.200
probability of concluding that it is not (the target of this value was 0.200). A total of 78
patients have to be enrolled, 13 in the first stage and 65 in the second stage. The Trial
Advisory Committee (TAC) will monitor the accrual and the cytogenetic response status every
3 months and will stop the study if the loss of the CCgR is more than 15.4% and 9.2% in the
first and second stage, respectively.
Trial Time Trial time is 12 months. Thereafter, all patients are followed by standard
hematologic, cytogenetic and molecular criteria, indefinitely.
Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
The proportion of patients who remain in CCgR with INTERIM given for one year.
Prof Domenico Russo, MD
Chair of Haematology, Brescia University
Italy: Ministry of Health