Clinical Trials /

Nilotinib Treatment-free Remission Study in CML (Chronic Myeloid Leukemia) Patients

NCT01784068

Description:

The main purpose of the study is to investigate whether nilotinib treatment can be safely suspended with no recurrence of CML in selected patients who responded optimally on this treatment

Related Conditions:
  • Chronic Myeloid Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nilotinib Treatment-free Remission Study in CML (Chronic Myeloid Leukemia) Patients
  • Official Title: A Single-arm, Multicenter, Nilotinib Treatment-free Remission Study in Patients With BCR-ABL1 Positive Chronic Myelogenous Leukemia in Chronic Phase Who Have Achieved Durable Minimal Residual Disease (MRD) Status on First Line Nilotinib Treatment.

Clinical Trial IDs

  • ORG STUDY ID: CAMN107I2201
  • NCT ID: NCT01784068

Conditions

  • Chronic Myelogenous Leukemia

Interventions

DrugSynonymsArms
Nilotinib followed by treatment-freeNilotinib followed by treatment-free

Purpose

The main purpose of the study is to investigate whether nilotinib treatment can be safely suspended with no recurrence of CML in selected patients who responded optimally on this treatment

Trial Arms

NameTypeDescriptionInterventions
Nilotinib followed by treatment-freeExperimentalPatients who have received a minimum of 2 years of first line nilotinib treatment and with pre-screen PCR results in ≥ MR4.5 will enter the consolidation phase of the study (52 weeks - nilotinib 300 mg BID). Patients with Minimal Residual Disease (MRD) at the end of this phase will enter the Treatment-Free Remission (TFR) phase where no treatment is given. Non eligible patients will enter the continuation phase of the study. Patients with MRD at the end of the continuation phase will enter the TFR-2 phase of the study where no treatment is given. Non eligible patients will enter the prolonged continuation phase of the study. If at any time during TFR or TFR-2 the patient loses MMR, nilotinib treatment will be immediately re-initiated (nilotinib 300 mg BID).
  • Nilotinib followed by treatment-free

Eligibility Criteria

        Inclusion Criteria:

          -  Minimum of 2 calendar years of nilotinib treatment with at least the last 12 months
             of nilotinib treatment prior to pre-screening at approved total dialy dose of 600 mg
             BID or at a reduced dose of 400 mg QD if required from the perspective of tolerance
             for BCR-ABL positive CML in documented chronic phase at the time of diagnosis

          -  Evidence of typical BCR-ABL transcripts (b3a2 and/or b2a2) at the time of CML-CP
             diagnosis i.e. prior to first start of TKI treatment which are amenable to
             standardized RT-PCR quantification"

          -  Patient in MR4.5 at prescreening at Novartis designated lab

          -  ECOG performance status of 0-2

          -  Adequate end organ function as defined by:

               -  Direct bilirubin ≤ 1.5 x ULN except for i) patients 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 i.e. equivalent to ≤ Grade 1 NCI-CTCAE v.4.03

               -  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 within normal limits or corrected
             to be within normal limits with supplements prior to first dose of study medication:

               -  Potassium (suggested keep to prevent issues with QT and/or rhythm abnormalities)

               -  Magnesium (suggested keep to prevent issues with QT and/or rhythm abnormalities)

               -  Total calcium (corrected for serum albumin)

          -  Patients must have normal marrow function as defined:

               -  Absolute Neutrophil Count (ANC) ≥ 1.5 x 10E9/L

               -  Hemoglobin ≥ 9.0 g/dL

               -  Platelets ≥ 100 x 10E9/L

        Exclusion Criteria:

          -  Previous treatment with BCR-ABL inhibitors other than nilotinib for more than a total
             cumulative duration of 4 weeks

          -  Previous treatment with alpha-interferon of any duration

          -  Previous anticancer agents for CML other than nilotinib except for cytoreduction
             after CML diagnosis until up to 4 weeks after first dose of nilotinib

          -  Known second chronic phase of CML after previous progression to AP/BC

          -  Poorly controlled diabetes mellitus (defined as HbA1c > 9%)

          -  Impaired cardiac function including any one of the following:

               -  LVEF < 45% or below the institutional lower limit of the normal range (whichever
                  is higher)

               -  Inability to determine the QT interval on ECG, except for patients with evidence
                  of measurable QT interval at the time of CML diagnosis (e.g. prior to first
                  start of TKI treatment) and who have no documented clinical signs of
                  cardiovascular disease and/or clinical signs of conduction abnormality.

               -  Complete left bundle branch block

               -  Right bundle branch block plus left anterior or posterior hemiblock

               -  Use of a ventricular-paced pacemaker

               -  Congenital 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

               -  QTc > 450 msec on the average of three serial 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-tested for QTc.This
                  exclusion criterion is not applicable for patients with non-measurable QT
                  interval who have evidence of measurable QT interval at the time of CML
                  diagnosis (e.g. prior to first start of TKI treatment) and who have no
                  documented clinical signs of cardiovascular disease and/or clinical signs of
                  conduction abnormality.

               -  History or clinical signs of myocardial infarction within 1 year of study entry

               -  History of unstable angina within 1 year of study entry

               -  Other clinically significant heart disease (e.g. congestive heart failure,
                  cardiomyopathy or uncontrolled hypertension)

          -  History of acute pancreatitis within 1 year of study entry or past medical history of
             chronic pancreatitis

          -  Known presence of significant congenital or acquired bleeding disorder unrelated to
             cancer

          -  History of another active malignancy within 5 years prior to study entry with the
             exception of previous or concomitant basal cell skin cancer and previous carcinoma in
             situ treated curatively

          -  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 starting study drug. See Appendix 1 for a list of these medications. This
             list may not be exhaustive.

          -  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 starting study drug. These herbal
             medicines may include Echinacea, (including E. purpurea, E. angustifolia and E.
             pallida), Piperine, Artemisinin, St. John's Wort, and Ginkgo.

          -  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 starting study drug.
             (Please see http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm
             for a list of agents that prolong the QT interval)

          -  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)

          -  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.

          -  Women of child-bearing potential, defined as all women physiologically capable of
             becoming pregnant, unless they are using highly effective methods of contraception
             during the study and for 14 days after the final dose of nilotinib. Highly effective
             contraception is defined as either:

               -  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) 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 enrolling). For female patients
                  on the study the vasectomized male partner should be the sole partner for that
                  patient.

               -  Use of a combination of any two of the following:

                    1. Use of oral, injected or implanted hormonal methods of contraception or
                       other forms of hormonal contraception that have comparable efficacy
                       (failure rate <1%), for example hormone vaginal ring or transdermal hormone
                       contraception.

                    2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

                    3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or
                       cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
                       suppository In case of use of oral contraception women should have been
                       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) 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 suspects being pregnant during the study or within
        30 days after the final dose of nilotinib, the Study Doctor needs to be informed
        immediately and ongoing study treatment with nilotinib has to be stopped immediately.

        Other protocol-defined inclusion/exclusion criteria may apply.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of patients who are in MMR (major molecular response) at 48 weeks after starting the treatment-free remission (TFR) phase
Time Frame:48 weeks
Safety Issue:
Description:Primary endpoint is the proportion of patients who are in MMR at 48 weeks after starting the TFR phase and is calculated by dividing the number of patients with MMR at 48 weeks after starting the TFR phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase by the number of patients entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders

Secondary Outcome Measures

Measure:Percentage of patients who are in MR4.5 (BCR-ABL ≤ 0.0032% IS) at 48 weeks after starting the TFR phase
Time Frame:48 weeks
Safety Issue:
Description:Proportion of patients who are in MR4.5 at 48 weeks after starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 48 weeks after starting the TFR phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders. MR4.5 = log reductions of the BCR-ABR transcript load in blood as a measurement of deep molecular response of the CML clone to treatment.
Measure:Percentage of patients who are in MMR at 96, 144,192 and 264 weeks after starting the TFR phase
Time Frame:96, 144, 192 and 264 weeks
Safety Issue:
Description:Proportion of patients who are in MMR at 96, 144, 192 and 264 weeks after starting the TFR phase is calculated by dividing the number of patients with MMR at 96, 144, 192 and 264 weeks after starting the TFR phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 96, 144, 192 and 264 weeks after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders
Measure:Percentage of patients who are in MR4.5 at 96, 144, 192 and 264 weeks after starting the TFR phase
Time Frame:96, 144, 192 and 264 weeks
Safety Issue:
Description:Proportion of patients who are in MR4.5 at 96, 144, 192 and 264 weeks after starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 96, 144, 192 and 264 weeks after starting the TFR phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 96, 144, 192 and 264 weeks after starting the TFR phase by the number of patients who entered the TFR phase. Patients who required re-initiation of treatment will be considered as non-responders
Measure:Percentage of patients in MMR at 48, 96, 144, 192 and 264 weeks after starting the TFR phase of nilotinib
Time Frame:48, 96, 144, 192 and 264 weeks
Safety Issue:
Description:Proportion of patients who are in MMR at 48, 96, 144, 192 and 264 weeks after starting the TFR phase is calculated by dividing the number of patients with MMR at 48, 96, 144, 192 and 264 weeks after starting the TFR phase by the number of patients who entered the TFR phase. Patients who are re-initiated with nilotinib but have less than 12 weeks of re-initiation of treatment will be excluded from the analysis
Measure:Percentage of patients in MR4.5 at 48, 96, 144, 192 and 264 weeks after starting the TFR phase of nilotinib
Time Frame:48, 96, 144, 192 and 264 weeks
Safety Issue:
Description:Proportion of patients who are in MR4.5 at 48, 96, 144, 192 and 264 weeks after starting the TFR phase is calculated by dividing the number of patients with MR4.5 at 48, 96, 144, 192 and 264 weeks after starting the TFR phase by the number of patients who entered the TFR phase. Patients who are re-initiated with nilotinib but have less than 12 weeks of re-initiation of treatment will be excluded from the analysis
Measure:Percentage of patients who achieve MMR within 12 weeks of re-treatment with nilotinib
Time Frame:12 weeks
Safety Issue:
Description:Proportion of patients who achieve MMR within 12 weeks of re-initiation of nilotinib is calculated by dividing the number of patients who are in MMR at least at one assessment within 12 weeks after re-start of nilotinib treatment by the number of patients who are re-initiated for at least 12 weeks
Measure:Kinetics of BCR-ABL transcript after re-start of nilotinib therapy
Time Frame:Every 4 weeks up to week 24 and every 12 weeks thereafter up to 264 after last patient has entered the TFR
Safety Issue:
Description:Descriptive statistics of BCR-ABL levels (IS) over time after re-start of nilotinib therapy up to 264 weks after the last patient has entered TFR
Measure:Duration of re-initiated treatment required to regain MMR after loss of MMR
Time Frame:Every 4 weeks up to week 24 and every 12 weeks therefater up to 264 weks after the last patient has entered TFR
Safety Issue:
Description:Defined as time from date of start of re-initiation of treatment after loss of MMR to the date of first achievement of MMR. Patients who do not regain MMR after re-initiation of treatment on or before the cut-off date, duration will be censored at the date of last PCR assessment
Measure:Duration of re-initiated treatment required to regain MR4.5 after loss of MMR
Time Frame:Every 4 weeks up to week 24 and every 12 weeks thereafter up to 264 weks after the last patient has entered TFR
Safety Issue:
Description:Defined as the time from start of re-initiation of treatment after loss of MMR to the first achievement of MR4. Patients who do not regain MR4.5 after re-initiation of treatment on or before the cut-off date, duration will be censored at the date of last PCR assessment
Measure:Treatment-free survival (TFS) after the start of the TFR phase
Time Frame:Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks in TFR and every 12 weeks in the last period of 168 weeks of the TFR
Safety Issue:
Description:TFS is defined as the time from the start of the TFR phase to the earliest occurrence of loss of MMR, re-initiation of treatment due to any cause, progression of AP/BC or death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment (PCR, cytogenetic, hematologic or extramedullary). A TFS sensitivity analysis will be conducted to consider discontinuation from TFR phase due to any reason as a TFS event, in addition to the TFS events as defined above.
Measure:Progression-free survival (PFS) after the start of the TFR phase
Time Frame:Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks of TFR and every 12 weeks in the last period of 168 weeks of the TFR
Safety Issue:
Description:PFS is defined as the time from the start of the TFR phase to the earliest occurrence of progression to AP/BC or death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment (cytogenetic, hematologic or extramedullary) for patients who are still on study and at the date of last contact for patients who are in follow-up
Measure:Overall survival (OS) after the start of the TFR phase
Time Frame:Every 4 weeks in the first period of 48 weeks of the TFR, every 6 weeks in the second period of 48 weeks of TFR and every 12 weeks in the last period of 168 weeks of the TFR
Safety Issue:
Description:OS is defined as the time from start of the TFR phase to death due to any cause. For patients without any event on or before the cut-off date, survival time will be censored at the date of their last assessment for patients who are still on study and at the date of last contact for patients who are in follow-up
Measure:Safety profile during the nilotinib treatment consolidation phase, during the TFR phase and during re-initiation treatment with nilotinib
Time Frame:Every 4 weeks in the treatment consolidation and during the first 24 weeks of the re-initaion phase, every 12 weeks thereafter. Every 4, 6 and 12 weeks respectively in the first and second period of 48 weeks and in the last period of 168 weeks of the TFR
Safety Issue:
Description:Safety profile includes type, frequency and severity of adverse events, laboratory abnormalities and clinically notable ECG and other safety parameters during the nilotinib treatment consolidation phase, during the TFR phase and during re-initiation of treatment with nilotinib
Measure:Proportion of patients who develop T3151, E255K/V, Y253H, F359V/C/I mutations on study or any other BCR-ABL mutations in patients who lost MMR after nilotinib suspension
Time Frame:Every 3 months in patients who lost MMR until the result is negative or up to 192 weeks after the last patient entered TFR. On average 3 analyses (every 3 months or up to 264 weeks after the last patient has entered TFR.)
Safety Issue:
Description:Proportion will be calculated by dividing the number of patients who developT315I, E255K/V, Y253H, F359V/C/I mutations after nilotinib suspension by the number of patients who lost MMR

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • Ph+ CML-CP
  • chronic phase
  • nilotinib treatment
  • 2 years treatment
  • MR 4.5
  • Loss of MR 4
  • Loss of MMR

Last Updated

June 26, 2017