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Treatment-free Remission After Achieving Sustained MR4.5 on Nilotinib (ENESTop) (ENESTop)

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ClinicalTrials.gov Identifier: NCT01698905
Recruitment Status : Active, not recruiting
First Posted : October 3, 2012
Last Update Posted : September 18, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
A clinical research study to find out if it is safe to stop the drug nilotinib (Tasigna) in chronic myeloid leukemia (CML) patients. Patients who started treatment with imatinib (Gleevec) when they were first diagnosed with CML, then switched to nilotinib (Tasigna) for at least 2 years with the combined time on imatinib (Gleevec) and nilotinib (Tasigna) for at least 3 years and have very small amount of leukemia cells remaining after the nilotinib (Tasigna) treatment will qualify for the study.

Condition or disease Intervention/treatment Phase
Chronic Myeloid Leukemia Drug: nilotinib Phase 2

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 166 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official 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
Actual Study Start Date : December 20, 2012
Actual Primary Completion Date : November 26, 2015
Estimated Study Completion Date : February 6, 2025


Arm Intervention/treatment
Experimental: nilotinib
70 patients who maintain MR4.5 during the one year nilotinib consolidation phase will stop treatment when they enter the treatment-free remission (TFR) phase
Drug: nilotinib
Nilotinib will be labeled as AMN107 and supplied as 150 mg and/or 200 mg hard gelatin capsule. Nilotinib will not be dosed by weight or body surface area. Nilotinib will be administered orally at 300 mg twice daily (BID) or 400 mg BID, at approximately 12 hour intervals, and must not be taken with food. The capsules should be swallowed whole with water. No food should be consumed for at least 2 hours before the dose is taken and no additional food should be consumed for at least one hour after the dose is taken. Patients who were previously treated with 400 mg BID, and required subsequent permanent dose reduction to 400 mg QD will be allowed to enter this study on the same dose, 400 mg once daily.




Primary Outcome Measures :
  1. Percentage of patients in Treatment Free Remission (TFR) within 48 weeks [ Time Frame: First 48 weeks following nilotinib cessation. ]
    TFR is defined as no confirmed loss of MR4 (Molecular response 4.0 log reduction from baseline) or loss of MMR (major molecular response) and no re-starting of nilotinib therapy within 12 months following cessation of nilotinib. Confirmed loss of MR4 is two consecutive BCR-ABL > 0.01% IS. Loss of MMR does not require confirmationTFR is calculated by dividing the number of patients with no documented confirmed loss of MR4, no documented loss of MMR and no re-starting of nilotinib therapy in the first 48 weeks after starting nilotinib TFR phase by the number of patients who entered nilotinib TFR phase.


Secondary Outcome Measures :
  1. Percentage of patients in Treatment Free Remission (TFR) within 96, 144, 192, 264 weeks and within 6,7,8,9 and 10 years [ Time Frame: 96, 144, 192, 264 weeks and within 6,7,8,9 and 10 years following nilotinib cessation ]
    TFR is defined as no confirmed loss of MR4 (molecular response 4.0 log reduction from baseline) or loss of MMR (major molecular response) and no re-starting of nilotinib therapy within 12 months following cessation of nilotinib. Confirmed loss of MR4 is two consecutive BCR-ABL > 0.01% IS. Loss of MMR does not require confirmation.TFR is calculated by dividing the number of patients with no documented confirmed loss of MR4, no documented loss of MMR and no re-starting of nilotinib therapy in the first 96, 144, 192, 264 weeks and within 6,7,8,9 and 10 years after starting nilotinib TFR phase by the number of patients who entered nilotinib TFR phase.

  2. Progression free survival (PFS) to Accelerated phase/Blast crisis (AP/BC) or death [ Time Frame: nilotinib cessation up to approximately 580 weeks ]
    Kaplan-Meier (KM) estimation of PFS. PFS is measured from the date of start of nilotinib TFR phase (cessation of nilotinib) to the date of the earliest of the event: progression to AP/BC, or death from any cause. Patients not known to have recurred or died on or before the cut-off date for the KM analysis will have their PFS interval right-censored at the earlier of the date of their last assessment (cytogenetic, hematology or extramedullary) for patients who are still on study and at the date of last contact for patients are in follow-up.

  3. Treatment free survival (TFS) [ Time Frame: nilotinib cessation up to approximately 580 weeks ]
    TFS is measured from the date of the start of the nilotinib TFR phase to the date of the earliest of the following: loss of MMR, confirmed loss of MR4, re-start of nilotinib treatment, progression to AP/BC or death from any cause. Patients not known to have had any of the events or died on or before the cut-off date for the KM analysis will have their TFS interval right-censored at the earlier of the date of their last assessment (PCR, cytogenetic, hematology or extramedullary) for patients who are still on study and at the date of last contact for patients are in follow-up.

  4. Overall survival (OS) [ Time Frame: nilotinib cessation up to approximately 580 weeks ]
    Kaplan-Meier (KM) estimation of OS. OS is measured from the date of start of nilotinib TFR phase to the date of death from any cause. If a patient is not known to have died, survival will be censored at the date of last contact.

  5. Change in BCR-ABL (oncoprotein product of BCR-ABL fusion gene) transcripts after re-start of nilotinib therapy [ Time Frame: re-start of nilotinib up to approximately 48 weeks ]
    Descriptive statistics of BCR-ABL over time after re-start of nilotinib therapy. ABL= Abelson leukemia virus and BCR=Break point cluster region

  6. Percentage of patients with stable MMR in nilotinib re-initiation phase [ Time Frame: start of nilotinib in re-initiation phase up to approximately 432 weeks ]
    Percentage of patients who are in stable MMR (stable MMR=BCR-ABL ≤ 0.1% IS) at 48, 96, 144, 192, 240,288 ,336, 384, and 432 weeks after achievement of that response in the nilotinib re-initiation phase for 48, 96, 144, 192, 240,288 ,336, 384, and 432 weeks is calculated by dividing the number of patients achieving MMR any time during the nilotinib re-initiation phase and having the same response at 48, 96, 144, 192, 240,288,336, 384, and 432 weeks after the first achievement of MMR, irrespective of whether there is loss of MMR in between, by the number of patients who achieved MMR at any time during the nilotinib re-initiation phase

  7. Percentage of patients with stable MR4 in nilotinib re-initiation phase [ Time Frame: start of nilotinib in re-initiation phase up to approximately 432 weeks ]
    Percentage of patients who are in stable MR4 (stable MR4=BCR-ABL ≤ 0.01% IS) at 48, 96, 144, 192, 240,288 ,336, 384, and 432 weeks after achievement of that response in the nilotinib re-initiation phase for 48, 96, 144, 192, 240,288 ,336, 384, and 432 weeks is calculated by dividing the number of patients achieving MR4 any time during the nilotinib re-initiation phase and having the same response at 48, 96, 144, 192, 240,288,336, 384, and 432 weeks after the first achievement of MR4, irrespective of whether there is loss of MR4 in between, by the number of patients who achieved MR4 at any time during the nilotinib re-initiation phase

  8. Percentage of patients with stable MR4.5 in nilotinib re-initiation phase [ Time Frame: start of nilotinib in re-initiation phase up to approximately 432 weeks ]
    Percentage of patients who are in stable MR4.5 (stable MR4.5=BCR-ABL ≤ 0.0032% IS) at 48, 96, 144, 192, 240,288 ,336, 384, and 432 weeks after achievement of that response in the nilotinib re-initiation phase for 48, 96, 144, 192, 240,288 ,336, 384, and 432 weeks is calculated by dividing the number of patients achieving MR4.5 any time during the nilotinib re-initiation phase and having the same response at 48, 96, 144, 192, 240,288,336, 384, and 432 weeks after the first achievement of MR4.5, irrespective of whether there is loss of MR4.5 in between, by the number of patients who achieved MR4.5 at any time during the nilotinib re-initiation phase



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

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:

    a. 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 and male/female sterilization defined as:

    • 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 and documented by follow up hormone level assessment
    • Male sterilization (at least 6 months prior to screening). For female patients on the study, study participation assumes the vasectomized male partner is the sole partner for that patient or b. A combination of any two of the following (i+ii or i+iii or ii+iii): i) Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository ii) 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 iii) Placement of an intrauterine device (IUD) or intrauterine system (IUS)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01698905


  Show 70 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT01698905     History of Changes
Other Study ID Numbers: CAMN107A2408
First Posted: October 3, 2012    Key Record Dates
Last Update Posted: September 18, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Phase II, single arm, open label, nilotinib, treatment-free remission, MR4.5, confirmed loss of MR4, loss of MMR, Ph+ CML-CP

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases