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NCT Number: NCT01743989

A Randomized Phase III Study to Assess the Effect of a Longer Duration of Consolidation Treatment With Nilotinib on TFR in CP CML.

This study aimed to assess the optimal duration of nilotinib 300 mg twice daily (BID) consolidation treatment in patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML), in order that patients remained in treatment-free remission (≥MR4.0) without molecular relapse 12 months after starting the Treatment-Free Remission (TFR) phase.

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Key information

Conditions

Philadelphia Chromosome Positive (PH+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) Bone Marrow Diseases Chronic Disease Disease Attributes Hematologic Diseases Hemic and Lymphatic Diseases Immune System Diseases Immunoproliferative Disorders Leukemia Leukemia, Lymphoid Leukemia, Myelogenous, Chronic, BCR-ABL Positive Leukemia, Myeloid Lymphatic Diseases Lymphoproliferative Disorders Myeloproliferative Disorders Neoplasms Neoplasms by Histologic Type Pathologic Processes Pathological Conditions, Signs and Symptoms Precursor Cell Lymphoblastic Leukemia-Lymphoma

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Novartis Investigative Site, Linz, Upper Austria, Austria

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About this study

This was a prospective, randomized, open-label, multicenter Phase III study. The study design was made up of 3 phases:

  • Nilotinib induction phase: 12 months
  • Nilotinib consolidation phase: 12 or 24 months, depending on randomization
  • Nilotinib treatment-free remission (TFR) phase: 24 or 36 months, depending on randomization.

Subjects were enrolled into the study and were treated with nilotinib 300mg twice daily (BID) for 24 months, during the induction (12 months) and consolidation (12 months) phases. At the end of the first 24 months of treatment, participants achieving a sustained molecular response (defined as ≥ MR4.0, in 4 out of 5 real-time quantitative polymerase chain reaction (RQ-PCR) assessments, including the last assessment, in the last 12 months) were randomized on a 1:1 basis to either:

  • suspend nilotinib treatment immediately and enter the TFR phase for 36 months (Nilotinib 24-month treatment arm), or
  • continue nilotinib treatment for a further 12 months (post-randomization consolidation phase), then suspend treatment and enter the TFR phase for 24 months (Nilotinib 36-month treatment arm).

Participants not achieving a sustained molecular response at 24 months from treatment start were not eligible for randomization and were treated at the discretion of the investigator according to standard practice. Information on survival, stem cell transplantation, and status of the patient's disease was collected until death or until 5 years from study entry, whichever came first. Additionally, for Nilotinib 36-month treatment arm, participants who did not achieve a sustained molecular response at 36 months from treatment start, discontinued from the study and were treated according to standard practice and followed up until death or until 5 years from study entry, whichever came first.

Participants relapsing during the TFR phase entered the nilotinib re-treatment phase of the study, and were re-treated with the same dose of nilotinib as they were on before the TFR phase. These patients remained on study until the completion of the 5-year study period unless prematurely withdrawn and discontinued from the study for any reason specified in the Protocol.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Key Inclusion Criteria:

  • Confirmed diagnosis of chronic phase Ph+ CML
  • Previous first-line treatment with imatinib for a minimum of 2 years;
  • Patient in complete cytogenetic response;

Key Exclusion Criteria:

  • Previous achievement of MR4.0 at study entry;
  • Previous treatment with other target cells inhibitors other than imatinib;
  • Patients with any history of detectable atypical Leukemia transcripts or patients with detectable atypical leukemia transcripts at screening;
  • Previous anticancer agents for Chronic myeloid leukemia other than imatinib except for cytoreduction;
  • 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;
  • History of other active malignancies within the 5 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively;
  • Patients who have not recovered from prior surgery;
  • Treatment with other investigational agents within 4 weeks of Day 1;
  • Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug

Other inclusion/exclusion criteria might apply.

Treatment and study plan

Nilotinib

Drug

Participants received a daily oral nilotinib dose of 300 mg BID, given as two 150 mg capsules BID.

Other names: AMN107

Primary outcomes

  1. Percentage of Participants Who Remained in Treatment Free Remission (TFR) Without Molecular Relapse 12 Months After Entering the TFR Phase

    Time frame: 12 months after entering the TFR phase, which is after 36 months from study treatment start for Nilotinib 24-month treatment arm and after 48 months from study treatment start for Nilotinib 36-month treatment arm

    Number of participants who remained in TFR (≥molecular response (MR) 4.0) without molecular relapse 12 months after entering the TFR phase (without re-starting nilotinib therapy) divided by the number of participants who entered the TFR phase and multiplied by 100.

    Molecular relapse during TFR is defined as the loss of major molecular response (MMR), or the confirmed loss of MR4.0 (defined by 3 consecutive tests less than MR4.0 assessed at 3 consecutive visits during TFR phase). Participants dropping out early from the study during the TFR phase were considered as unsuccessful TFR.

    Confidence intervals were calculated based on the Exact Clopper-Pearson method. MMR is defined as≥3.0 log reduction in BCR-ABL transcripts compared to the standardized baseline or ≤0.1% BCR-ABL.

    MR4.0 is defined as either detectable disease≤0.01% BCR-ABL or undetectable disease in cDNA with≥10,000 ABL transcripts

Secondary outcomes

  1. Cumulative Incidence of MMR During the Pre-randomization Induction/Consolidation Phase Among Participants Without That Response at Study Entry

    Time frame: From baseline up to 24 months after study treatment start

    Number of participants who were in MMR during pre-randomization induction/consolidation phase divided by the number of participants without that response at baseline and multiplied by 100.

    Confidence intervals were calculated based on the Exact Clopper-Pearson method. MMR is defined as ≥3.0 log reduction in BCR-ABL transcripts compared to the standardized baseline or ≤0.1% BCR-ABL.

  2. Cumulative Incidence of MMR During the Post-randomization Consolidation Phase Among Participants Without That Response at Study Entry

    Time frame: From randomization (month 24 after study treatment start) up to 36 months after study treatment start

    Number of participants who were in MMR during post-randomization consolidation phase divided by the number of participants without that response at baseline and multiplied by 100. Post-randomization consolidation phase corresponded to the 12-month additional treatment (after randomization) for Nilotinib 36-month treatment arm.

    Confidence intervals were calculated based on the Exact Clopper-Pearson method. MMR is defined as ≥3.0 log reduction in BCR-ABL transcripts compared to the standardized baseline or ≤0.1% BCR-ABL.

  3. Cumulative Incidence of MR4.0 During the Pre-randomization Induction/Consolidation Phase Among Participants Without That Response at Study Entry

    Time frame: From baseline up to 24 months after study treatment start

    Number of participants who were in MR4.0 during the pre-randomization induction/consolidation phase divided by the number of participants without that response at baseline and multiplied by 100.

    Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.0 is defined as either detectable disease ≤0.01% BCR-ABL IS or undetectable disease in cDNA with ≥10,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)

  4. Cumulative Incidence of MR4.0 During the Post-randomization Consolidation Phase Among Participants Without That Response at Study Entry

    Time frame: From randomization (month 24 after study treatment start) up to 36 months after study treatment start

    Number of participants who were in MR4.0 during the post-randomization consolidation phase divided by the number of participants without that response at baseline and multiplied by 100. Post-randomization consolidation phase corresponded to the 12-month additional treatment (after randomization) for Nilotinib 36-month treatment arm.

    Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.0 is defined as either detectable disease ≤0.01% BCR-ABL IS or undetectable disease in cDNA with ≥10,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)

  5. Cumulative Incidence of MR4.5 During the Pre-randomization Induction/Consolidation Phase Among Participants Without That Response at Study Entry

    Time frame: From baseline up to 24 months after study treatment start

    Number of participants who were in MR4.5 during the pre-randomization induction/consolidation phase divided by the number of participants without that response at baseline and multiplied by 100.

    Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.5 is defined as either detectable disease ≤ 0.0032% BCR-ABL IS; or undetectable disease within cDNA with ≥ 32,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)

  6. Cumulative Incidence of MR4.5 During the Post-randomization Consolidation Phase Among Participants Without That Response at Study Entry

    Time frame: From randomization (month 24 after study treatment start) up to 36 months after study treatment start

    Number of participants who were in MR4.5 during the post-randomization consolidation phase divided by the number of participants without that response at baseline and multiplied by 100. Post-randomization consolidation phase corresponded to the 12-month additional treatment (after randomization) for Nilotinib 36-month treatment arm.

    Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.5 is defined as either detectable disease ≤ 0.0032% BCR-ABL IS; or undetectable disease within cDNA with ≥ 32,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)

  7. Cumulative Incidence of MMR During the Pre-randomization Induction/Consolidation Phase

    Time frame: From baseline up to 24 months after study treatment start

    Number of participants who were in MMR during the pre-randomization induction/consolidation phase divided by the number of enrolled participants and multiplied by 100.

    Confidence intervals were calculated based on the Exact Clopper-Pearson method. MMR is defined as ≥3.0 log reduction in BCR-ABL transcripts compared to the standardized baseline or ≤0.1% BCR-ABL.

  8. Cumulative Incidence of MMR During the Post-randomization Consolidation Phase

    Time frame: From randomization (month 24 after study treatment start) up to 36 months after study treatment start

    Number of participants who were in MMR during the post-randomization consolidation phase divided by the number of enrolled participants and multiplied by 100. Post-randomization consolidation phase corresponded to the 12-month additional treatment (after randomization) for Nilotinib 36-month treatment arm.

    Confidence intervals were calculated based on the Exact Clopper-Pearson method. MMR is defined as ≥3.0 log reduction in BCR-ABL transcripts compared to the standardized baseline or ≤0.1% BCR-ABL.

  9. Cumulative Incidence of MR4.0 During the Pre-randomization Induction/Consolidation Phase

    Time frame: From baseline up to 24 months after study treatment start

    Number of participants who were in MR4.0 during the pre-randomization induction/consolidation phase divided by the number of enrolled participants and multiplied by 100.

    Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.0 is defined as either detectable disease ≤0.01% BCR-ABL IS or undetectable disease in cDNA with ≥10,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)

  10. Cumulative Incidence of MR4.0 During the Post-randomization Consolidation Phase

    Time frame: From randomization (month 24 after study treatment start) up to 36 months after study treatment start

    Number of participants who were in MR4.0 during the post-randomization consolidation phase divided by the number of enrolled participants and multiplied by 100. Post-randomization consolidation phase corresponded to the 12-month additional treatment (after randomization) for Nilotinib 36-month treatment arm.

    Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.0 is defined as either detectable disease ≤0.01% BCR-ABL IS or undetectable disease in cDNA with ≥10,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)

  11. Cumulative Incidence of MR4.5 During the Pre-randomization Induction/Consolidation Phase

    Time frame: From baseline up to 24 months after study treatment start

    Number of participants who were in MR4.5 during the pre-randomization induction/consolidation phase divided by the number of enrolled participants and multiplied by 100.

    Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.5 is defined as either detectable disease ≤ 0.0032% BCR-ABL IS; or undetectable disease within cDNA with ≥ 32,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)

  12. Cumulative Incidence of MR4.5 During the Post-randomization Consolidation Phase

    Time frame: From randomization (month 24 after study treatment start) up to 36 months after study treatment start

    Number of participants who were in MR4.5 during the post-randomization consolidation phase divided by the number of enrolled participants and multiplied by 100. Post-randomization consolidation phase corresponded to the 12-month additional treatment (after randomization) for Nilotinib 36-month treatment arm.

    Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.5 is defined as either detectable disease ≤ 0.0032% BCR-ABL IS; or undetectable disease within cDNA with ≥ 32,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)

  13. Percentage of Participants Who Were in MMR During TFR Phase

    Time frame: From Month 1 after entering TFR phase up to 24 months after entering TFR phase for Nilotinib 36-month treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-month treatment arm

    Number of participants who were in MMR at selected timepoints divided by the number of participants in the TFR phase and multiplied by 100. Participants randomized in Nilotinib 36-month treatment arm had a maximum of 24 months of TFR phase, whereas participants randomized in Nilotinib 24-month treatment arm had a maximum of 36 months of TFR phase.

    Confidence intervals were calculated based on the Exact Clopper-Pearson method. MMR is defined as ≥3.0 log reduction in BCR-ABL transcripts compared to the standardized baseline or ≤0.1% BCR-ABL.

  14. Percentage of Participants Who Were in MR4.0 During the TFR Phase

    Time frame: From Month 1 after entering TFR phase up to 24 months after entering TFR phase for Nilotininb 36-months treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-months treatment arm

    Number of participants who were in MR4.0 at selected timepoints divided by the number of participants in the TFR phase and multiplied by 100. Participants randomized in Nilotinib 36-month treatment arm had a maximum of 24 months of TFR phase, whereas participants randomized in Nilotinib 24-month treatment arm had a maximum of 36 months of TFR phase.

    Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.0 is defined as either detectable disease ≤0.01% BCR-ABL IS or undetectable disease in cDNA with ≥10,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)

  15. Percentage of Participants Who Were in MR4.5 During the TFR Phase

    Time frame: From Month 1 after entering TFR phase up to 24 months after entering TFR phase for Nilotininb 36-month treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-month treatment arm

    Number of participants who were in MR4.5 at selected timepoints divided by the number of participants in the TFR phase and multiplied by 100. Participants randomized in Nilotinib 36-month treatment arm had a maximum of 24 months of TFR phase, whereas participants randomized in Nilotinib 24-month treatment arm had a maximum of 36 months of TFR phase.

    Confidence intervals were calculated based on the Exact Clopper-Pearson method. MR4.5 is defined as either detectable disease ≤ 0.0032% BCR-ABL IS; or undetectable disease within cDNA with ≥ 32,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)

  16. BCR-ABL Ratio (Expressed as a Percentage) During the Induction/Consolidation Phase

    Time frame: From baseline up to 24 months after study treatment start for Nilotinib 24-month treatment arm and Not randomized participants; and up to 36 months after study treatment start for Nilotinib 36-month treatment arm.

    BCR-ABL transcript ratio by international scale (IS) (expressed as a percentage) during the induction/consolidation phase. Participants randomized to Nilotinib 36-month treatment arm had 12-month additional consolidation phase (post-randomization).

  17. BCR-ABL Ratio (Expressed as a Percentage) During the TFR Phase

    Time frame: From Month 1 after entering TFR phase up to 24 months after entering TFR phase for Nilotinib 36-month treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-month treatment arm

    BCR-ABL/control gene (ABL) transcript ratio by international scale (IS) (expressed as a percentage) during the TFR phase. BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes.

    Participants randomized in Nilotinib 36-month treatment arm had a maximum of 24 months of TFR phase, whereas participants randomized in Nilotinib 24-month treatment arm had a maximum of 36 months of TFR phase.

  18. BCR-ABL Ratio (Expressed as a Percentage) During the Nilotinib Re-treatment Phase

    Time frame: From Day 1 after entering the re-treatment phase up to 24 months after entering re-treatment phase for Nilotinib 36-month treatment arm and 36 months after entering the re-treatment phase for Nilotinib 24-month treatment arm

    BCR-ABL/control gene (ABL) transcript ratio by international scale (IS) (expressed as a percentage) during the nilotinib re-treatment phase. BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes.

  19. Progression-free Survival (PFS) During the TFR Phase of the Study.

    Time frame: From the start of the TFR phase to progression to AP/BC or death up to 24 months after entering TFR phase for Nilotininb 36-month treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-month treatment arm

    PFS is defined as the time from the date of start of the nilotinib TFR phase to the date of acelerated phase/blast crisis (AP/BC) or death, whichever came first. Participants randomized in Nilotinib 36-month treatment arm had a maximum of 24 months of TFR phase, whereas participants randomized in Nilotini 24-month treatment arm had a maximum of 36 months of TFR phase.

    Patients not known to have recurred or died on or before the cut-off date for PFS analysis were censored at the date of their last assessment (cytogenetic, hematology or extramedullary) for patients who were on study, and at the date of last contact for patients who were in follow-up.

  20. Treatment -Free Survival (TFS) During the TFR Phase of the Study

    Time frame: From the start of the TFR phase to the date of occurrence of treatment-free survival event, up to 24 months after entering TFR phase for Nilotinib 36-month treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-month treatment arm

    TFS is defined as the time from the start of the TFR phase to the date of the earliest of the following: loss of MMR, confirmed loss of MR4.0,re-start of nilotinib treatment, progression to AP/BC, or death from any cause. Patients not known to have had any of the events on or before the cut-off date were censored at the earlier of the date of their last assessment for patients who were still on study and the date of last contact for patients who were in follow-up. Participants randomized in Nilotinib 36-month treatment arm had a maximum of 24 months of TFR phase, whereas participants randomized in Nilotinib 24-month treatment arm had a maximum of 36 months of TFR phase. MMR is defined as ≥3.0 log reduction in BCR-ABL transcripts compared to the standardized baseline or ≤0.1%BCR-ABL.

    MR4.0 is defined as either detectable disease ≤0.01%BCR-ABL IS or undetectable disease in cDNA with ≥10,000 ABL transcripts (numbers of ABL transcripts in the same volume of cDNA used to test for BCR-ABL)

  21. Overall Survival (OS) Rate During the TFR Phase of the Study.

    Time frame: From the start of the TFR phase to death due to any cause, assessed up to 24 months after entering TFR phase for Nilotinib 36-month treatment arm and up to 36 months after entering TFR phase for Nilotinib 24-month treatment arm

    OS is defined as the time from start of the TFR phase to the time of death due to any cause. Participants randomized in Nilotinib 36-month treatment arm had a maximum of 24 months of TFR phase, whereas participants randomized in Nilotini 24-month treatment arm had a maximum of 36 months of TFR phase.

    For participants 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.

Sponsors and collaborators

Lead sponsor

Novartis Pharmaceuticals

Industry

Registry information

Official study title

A Prospective, Randomized, Open Label, Two Arm Phase III Study to Evaluate Treatment Free Remission (TFR) Rate in Patients With Philadelphia-positive CML After Two Different Durations of Consolidation Treatment With Nilotinib 300mg BID.

Acronym: ENESTPath

Important dates

Study start
2013
Primary completion
2020
Study completion
2020
First posted
Dec 6, 2012
Registry last updated
Jul 15, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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