A Phase II, Single Arm, Multicenter Study of Nilotinib in Combination With Pegylated Interferon-α2b in Patients With Suboptimal Molecular Response or Stable Detectable Molecular Residual Disease After at Least Two Years of Imatinib Treatment (NordDutchCML009)
Overview
- Phase
- Phase 2
- Intervention
- Nilotinib
- Conditions
- Chronic Myeloid Leukemia
- Sponsor
- Amsterdam UMC, location VUmc
- Enrollment
- 20
- Locations
- 5
- Primary Endpoint
- the proportion of patients achieving confirmed MR4.0.
- Status
- Terminated
- Last Updated
- 7 years ago
Overview
Brief Summary
The purpose of this trial is to assess the effect of switching CML patients, who have been treated with imatinib ≥ 2 years and who have stable detectable molecular residual disease between 0.01-1.0% (IS), to the combination of Nilotinib and PegIFN, in terms of the proportion of patients who achieve confirmed MR4.0.
Detailed Description
Study phase: Phase II. Patient population: Patients with suboptimal molecular response or stable detectable molecular residual disease after ≥ 2 years of treatment with imatinib (i.e. BCR ABL level between 0.01% and 1% IS). Study objective: To assess the effect of switching CML patients, who have been treated with imatinib ≥ 2 years and who have stable detectable molecular residual disease between 0.01-1.0% (IS), to the combination of Nilotinib and PegIFN, in terms of the proportion of patients who achieve confirmed MR4.0. Study design: Single arm, open label, multicenter study to assess the efficacy, safety and tolerability of nilotinib 300 mg BID, alone and in combination with PegIFN 25 - 40 μg/week in patients not in CMR. Patients will be treated with nilotinib 300 mg BID at the beginning of the study to establish the tolerability before adding PegIFN. Combination treatment will be continued until Month 12, which is followed by monotherapy phase of nilotinib 300 mg BID. Overall study duration for the individual patient is 24 months.
Investigators
J.J.W.M. Janssen
MD, PhD
Amsterdam UMC, location VUmc
Eligibility Criteria
Inclusion Criteria
- •Patients ≥ 18 years
- •At diagnosis CML in chronic phase
- •Documented complete cytogenetic response by bone marrow (standard cytogenetics) or peripheral blood BCR ABL \<1% IS
- •Persistent disease demonstrated by two PCR positive tests (i.e. BCR ABL level between 0.01% and 1% IS) which have been performed during the past 9 months and more than 10 weeks apart. One of these should be performed within 1 month of registration
- •Treatment with imatinib for at least 2 years with 400 mg and at a stable dose (i.e. the dose has not changed in the previous 6 months)
- •No other current or planned anti leukemia therapies
- •ECOG Performance status 0,1, or 2
- •Adequate organ function as defined by:
- •Total bilirubin \<1.5 x ULN. Does not apply to patients with isolated hyperbilirubinemia (e.g. Gilbert's disease) grade \<
- •ASAT and ALAT \<2.5 x ULN.
Exclusion Criteria
- •Prior accelerated phase or blast crisis.
- •Patient has received another investigational agent within last 6 months.
- •Previous treatment with nilotinib or dasatinib.
- •Prior stem cell transplantation.
- •Impaired cardiac function including any one of the following:
- •Inability to monitor the QT/QTc interval on ECG.
- •Long QT syndrome or a known family history of long QT syndrome.
- •Clinically significant resting brachycardia (\<50 bpm).
- •QTc \>450 msec on baseline ECG (using the QTcF formula). If QTcF \>450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re screened for QTc.
- •Myocardial infarction within 12 months prior to starting study.
Arms & Interventions
Nilotinib, Pegylated interferon α2b
Patients will be treated with nilotinib 300 mg BID during the first 3 months. Then the "combination phase" ensues with continued daily nilotinib 300 mg BID combined with PegIFN 25 ug/week for 3 months up to the Month 6 time point. If the patient has no more than grade 1 non-hematological toxicity or grade 2 hematological toxicity, the dose will be increased to 40 μg/w until Month 12. The "follow-up phase" with daily nilotinib 300 mg BID covers the next 12 months period (Month 12 to 24). until Month 12, which is followed by monotherapy phase of nilotinib 300 mg BID. Overall study duration for the individual patient is 24 months.
Intervention: Nilotinib
Nilotinib, Pegylated interferon α2b
Patients will be treated with nilotinib 300 mg BID during the first 3 months. Then the "combination phase" ensues with continued daily nilotinib 300 mg BID combined with PegIFN 25 ug/week for 3 months up to the Month 6 time point. If the patient has no more than grade 1 non-hematological toxicity or grade 2 hematological toxicity, the dose will be increased to 40 μg/w until Month 12. The "follow-up phase" with daily nilotinib 300 mg BID covers the next 12 months period (Month 12 to 24). until Month 12, which is followed by monotherapy phase of nilotinib 300 mg BID. Overall study duration for the individual patient is 24 months.
Intervention: Pegylated interferon α-2b
Outcomes
Primary Outcomes
the proportion of patients achieving confirmed MR4.0.
Time Frame: 12 months
An interim efficacy analysis will be prepared after 40 patients have completed 12 months study treatment.If already a sufficient number of patients have achieved the efficacy endpoint i.e. a 25% increase in MR4.0 rate (from 48% in ENEStcmr to 73% in this study). Using Fleming's method, we have indication of superior efficacy of the combination if 29 or more patients achieve MR4.0, and thereafter may stop inclusion in the study.
Secondary Outcomes
- the number of patients experiencing grade 3 or more adverse events(6 months)
- The proportion of patients who complete the planned 9 months of combination therapy with PegIFN (i.e. to Month 12 assessment).(12 months)