Clinical Trials /

Safety and Efficacy of Ponatinib Followed by Imatinib in Patients With Chronic Myelogenous Leukemia in Chronic Phase

NCT04070443

Description:

The investigators hypothesize that, in newly diagnosed de novo chronic phase CML patients, an induction treatment with ponatinib for 6 months should increase the rate of patients reaching a stable MR4.5 allowing cessation of imatinib treatment. The investigators proposal is to conduct a multicenter, Phase II trial to evaluate the safety, clinical and biological activity of an induction treatment with ponatinib for 6 months, followed by a consolidation treatment with imatinib in newly diagnosed de novo chronic phase CML patients.

Related Conditions:
  • Chronic Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Safety and Efficacy of Ponatinib Followed by Imatinib in Patients With Chronic Myelogenous Leukemia in Chronic Phase
  • Official Title: A Multicentre, Open-label Phase II Trial Evaluating the Safety and Efficacy of Ponatinib Induction Followed by Imatinib Maintenance in Adult Patients With Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) ≤ 65 Years

Clinical Trial IDs

  • ORG STUDY ID: ET18000120 (TIPI)
  • NCT ID: NCT04070443

Conditions

  • Philadelphia Chromosome Positive CML
  • BCR-ABL Positive Chronic Myelogenous Leukemia

Interventions

DrugSynonymsArms
PonatinibInduction phase with Ponatinib followed by Imatinib
ImatinibInduction phase with Ponatinib followed by Imatinib

Purpose

The investigators hypothesize that, in newly diagnosed de novo chronic phase CML patients, an induction treatment with ponatinib for 6 months should increase the rate of patients reaching a stable MR4.5 allowing cessation of imatinib treatment. The investigators proposal is to conduct a multicenter, Phase II trial to evaluate the safety, clinical and biological activity of an induction treatment with ponatinib for 6 months, followed by a consolidation treatment with imatinib in newly diagnosed de novo chronic phase CML patients.

Detailed Description

      TREATMENT PLAN :

      All eligible patients will be treated:

        -  During the induction Phase (Month 1 to Month 6) with ponatinib (30mg/day) single agent;
           then

        -  During the consolidation Phase (Month 7 to Month 36) with imatinib (400mg/day) single
           agent; then

        -  From M36 :

             -  Patients with stable MR4.5 (i.e. since at least 2 years) will enter in the TFR
                phase and will stop imatinib treatment. Thereafter, in case of MMR loss, imatinib
                will be re-introduced as per investigator judgement (including for dose).

             -  Patients without stable MR4.5 will continue imatinib treatment until stable MR4.5,
                or M60, PD, death, withdrawal of consent or overall trial completion. Such patients
                will be allowed to enter into the TFR phase as soon as a stable 2-year MR4.5 is
                reached: however, they will be considered as a failure for the primary endpoint
                analysis.

      STATISTICS :

      A total of 170 patients will be enrolled in this study.

      According to a Fleming design, with a P0=20% as minimal efficacy rate and P1=30% as an
      expected target, 156 patients should be enrolled, assuming an unilateral type I error alpha
      of 5% and 90% power. At the time of analysis, if at least 40 successes are observed among the
      156 evaluable patients, the treatment will be considered as interesting for further
      investigation in this indication. Considering that some patients may withdraw their consent
      before 36 months (about 10%), the investigators plan to enrol 170 patients in total.

      DATA ENTRY, DATA MANAGEMENT AND STUDY MONITORING All the data concerning the patients will be
      recorded in the electronic case report form (eCRF) throughout the study. Serious adverse
      event (SAE) and Adverse Event of Specific Interest (AESI) reporting will be also paper-based
      by e-mail and/or Fax.

      The sponsor will perform the study monitoring and will help the investigators to conduct the
      study in compliance with the clinical trial protocol, Good Clinical Practices (GCP) and local
      law requirements.
    

Trial Arms

NameTypeDescriptionInterventions
Induction phase with Ponatinib followed by ImatinibExperimentalPonatinib (Iclusig®) : Tyrosine Kinase Inhibitor (BCR-ABL); oral (tablets) : 30mg/day during 6 months (induction phase); Takeda & Incyte Biosciences. Imatinib (either Glivec® or any generic form) : Tyrosine Kinase Inhibitor (BCR-ABL, ABL, KIT and PDGFRA receptor tyrosine kinases); oral : 400 mg/day during at least 30 months (then, depending of MR4.5)
  • Ponatinib
  • Imatinib

Eligibility Criteria

        Inclusion Criteria:

          -  Male or female patients aged ≥18 and ≤65 years at time of inform consent signature.

          -  Cytologically confirmed CML, Philadelphia chromosome positive with or without
             additional chromosomal abnormalities and/or BCR-ABL positive (Major BCR (M-BCR)
             transcript exclusively), i. e. Cryptic Philadelphia chromosome patients can be
             enrolled:

               -  diagnosed within the past 2 months prior to D1 (i.e. within 60 days [± 7 days]
                  since the date of first cytogenetic analysis),

               -  in chronic phase defined by i) <15 % blasts in peripheral blood and bone marrow,
                  ii) < 30% blast plus promyelocytes in peripheral blood and bone marrow; iii) < 20
                  % basophils in peripheral blood and iv) ≥100 X 109 platelets/L in peripheral
                  blood,

               -  no extra-medullary disease.

               -  Intermediate or high EUTOS long-term survival Score.

          -  No prior treatment for CML with any tyrosine kinase inhibitor (eg. imatinib,
             dasatinib, nilotinib or bosutinib), or busulphan; interferon-alpha; homoharringtonine;
             cytosine arabinoside; or any other investigational agent; with the exception of
             hydroxyurea and/or anagrelide which are the only authorized prior treatments.

        Note: Hydroxyurea should be stopped at least 24 hours prior the initiation of ponatinib.

          -  Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1 or 2.

          -  Adequate organ functions as defined below according to lab tests performed within 7
             days before Day 1:

        Renal function:

        - Serum creatinine clearance ≥ 50 mL/min/1.73m2 according to CKD-EPDI formula or serum
        creatinine ≤ 2 upper limit of normal (ULN).

        Hepatic function:

          -  Serum bilirubin < 1.5 × ULN, with the following exception: Patients with known Gilbert
             disease who have serum bilirubin level ≤ 3 ULN may be enrolled.

          -  Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline
             phosphatase ≤ 2.5 ULN.

          -  Amylase or Lipase ≤ 1.5 × ULN Total cholesterol or triglycerides ≤1.5 ULN

               -  Women of child-bearing potential must have a negative serum pregnancy test within
                  7 days before study drug start and must agree to use an effective form of
                  contraception from the time of the negative pregnancy test up to 3 months after
                  the last dose of study treatments.

               -  Fertile men must agree to use an effective method of contraception during the
                  study and for up to 3 months after the last dose of study treatments.

               -  Patient should understand, sign, and date the written voluntary informed consent
                  form prior to any protocol-specific procedures performed. Patient should be able
                  and willing to comply with study visits and procedures as per protocol.

               -  Patients must be covered by a medical insurance.

        Exclusion Criteria:

          -  Any form of prior auto- or allo-hemopoietic stem cell transplant.

          -  Hypersensitivity to the active substance or to any of the excipients of ponatinib and
             imatinib (see respective IB/SmPC).

          -  Inability to take oral medication including malabsorption syndrome or other illness
             that could affect oral absorption of the study treatments (hereditary problems of
             galactose intolerance, the Lapp lactase deficiency or glucose-galactose
             malabsorption).

          -  Patients using, or requiring to use while on the study of any not permitted
             concomitant medications:

               -  Any approved anti-cancer systemic treatment including chemotherapy, targeted
                  therapy, immunotherapy or any biological therapy,

               -  Any investigational agents,

               -  Any treatment able to induce " torsades de pointes ",

               -  Any strong inducers and inhibitors of CYP3A4.

          -  Patients with a malignancy other than CP-CML within 5 years prior to Day 1 with the
             exception of those with a negligible risk of metastasis or death and treated with
             expected curative outcome (such as adequately treated in situ carcinoma of the cervix,
             basal or squamous cell skin cancer, localised prostate cancer or ductal in situ
             carcinoma treated surgically with curative intent).

          -  Patients with active B or C hepatitis infection. Notes: Patients with past Hepatitis B
             Virus (HBV) infection or resolved HBV infection (defined as having a negative
             hepatitis B surface antigen (HBsAg) test and a positive hepatitis B core antibody
             (HBcAb) test) are eligible.

        Patients with a positive HBcAb test must have a negative HBV DNA test at screening.

        Patients positive for Hepatitis C Virus (HCV) antibody are eligible only if polymerase
        chain reaction (PCR) is negative for HCV RNA.

          -  Patients with significant cardiovascular disease, such as New York Heart Association
             cardiac disease Class II or greater, myocardial infarction within 3 months prior to
             D1, unstable arrhythmias, unstable angina, peripheral arterial occlusive disease,
             venous thromboembolism or pulmonary embolism, brain stroke, evolutive ischemic
             cardiopathy; prolonged corrected QT interval (QTc) interval on baseline
             electrocardiogram (>450 msec on the Fridericia's correction) despite correction of
             predisposants factors; long congenital QT syndrome.

          -  Any of the following medical conditions despite adequate therapeutic management:

               -  Uncontrolled HTA despite adequate ongoing treatment.

               -  Diabetes with documented target organ damage.

          -  Pregnant or lactating women.
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Impact of Ponatinib induction treatment on the TFR rate
Time Frame:36 months after initiation of ponatinib
Safety Issue:
Description:Rate of patients reaching a stable MR4.5 (BCR-ABL (IS) ≤0.0032% with at least 32,000 copies of ABL) for ≥ 2 years at Month 36 after initiation of ponatinib.

Secondary Outcome Measures

Measure:Clinical activity of the proposed therapeutic strategy
Time Frame:up to 24 months after ponatinib initiation
Safety Issue:
Description:For all patients : Rate of patients with MR4.5; MR4.0 and MMR at 1, 2, 3, 6, 9, 12, 24 months after ponatinib initiation
Measure:Clinical activity of the proposed therapeutic strategy
Time Frame:up to 6 months after ponatinib initiation
Safety Issue:
Description:For all patients : Rate of patients with a BCR-ABL/ABL (IS) ≤ 10% and rate of patients with CCyR (or its molecular equivalent, BCR-ABL/ABL (IS) ≤ 10%) at 3 and 6 months after ponatinib initiation.
Measure:Clinical activity of the proposed therapeutic strategy
Time Frame:from the first intake of Ponatinib until one of this criteria is reached, assessed up to 5 years
Safety Issue:
Description:For all patients : Time to MR4.5, MR4.0 or MMR following ponatinib initiation
Measure:Clinical activity of the proposed therapeutic strategy
Time Frame:from the first intake of Ponatinib until one of this criteria is reached, assessed up to 5 years
Safety Issue:
Description:For all patients : Duration of MR4.5, MR4.0 or MMR
Measure:Clinical activity of the proposed therapeutic strategy
Time Frame:from the date of inclusion until the date of the first progression or date of death from any cause, whichever came first, assessed up to 5 years
Safety Issue:
Description:For all patients : Progression Free survival
Measure:Clinical activity of the proposed therapeutic strategy
Time Frame:From the date of inclusion until the date of death from any cause, whichever came first, assessed up to 5 years
Safety Issue:
Description:For all patients : Overall survival
Measure:Clinical activity of the proposed therapeutic strategy
Time Frame:3, 6, 9, 12 and 24 months after imatinib cessation
Safety Issue:
Description:For patients reaching TFR criteria and following imatinib cessation: Rate of successful TFR (patients sill with MR4.5) at 3, 6, 9, 12 and 24 months after imatinib cessation
Measure:Clinical activity of the proposed therapeutic strategy
Time Frame:from imatinib cessation until the date of progression/relapse, whichever came first, assessed up to 5 years
Safety Issue:
Description:For patients reaching TFR criteria and following imatinib cessation: Duration of TFR after imatinib cessation.
Measure:Clinical activity of the proposed therapeutic strategy
Time Frame:From the date of imatinib cessation until the date of death from any cause, assessed up to 5 years
Safety Issue:
Description:For patients reaching TFR criteria and following imatinib cessation: OS after imatinib cessation
Measure:Clinical activity of the proposed therapeutic strategy
Time Frame:from the date of imatinib cessation until the date of the first progression or date of death from any cause, whichever came first, assessed up to 5 years
Safety Issue:
Description:For patients reaching TFR criteria and following imatinib cessation: PFS after imatinib cessation
Measure:Clinical activity of the proposed therapeutic strategy
Time Frame:from the date of ponatinib initiation until the onset of the following events: loss of responses, accelerated phase or blast crisis at any time, death at any time from any cause; drug discontinuation due to adverse events, assessed up to 5 years
Safety Issue:
Description:For patients reaching TFR criteria and following imatinib cessation: Event-free survival according ELN recommendations
Measure:Clinical activity of the proposed therapeutic strategy
Time Frame:from the date of imatinib cessation until 30 days after the last study drugs intake or until initiation of a new anti-cancer treatment, whichever came first, assessed up to 5 years
Safety Issue:
Description:For patients reaching TFR criteria and following imatinib cessation: Rate of TKI-withdrawal syndrome after Imatinib cessation
Measure:Clinical activity of the proposed therapeutic strategy
Time Frame:from the date of imatinib re introduction until date of MMR or MR4.5, assessed up to 5 years
Safety Issue:
Description:For patients reaching TFR criteria and following imatinib cessation: Rate of MMR, MR4.0 and MR4.5 recovery in case of imatinib re-introduction (
Measure:Incidence of Adverse Events of the proposed therapeutic strategy
Time Frame:from the signature of the ICF and the first intake of study drug until 30 days after the last study drugs intake or until initiation of a new anti-cancer treatment, assessed up to 5 years
Safety Issue:
Description:Hematologic and non-hematologic AEs graded according to the NCI CTCAE v5.0 Incidence of arterial thrombotic events during the induction phase and during the consolidation phase.
Measure:Quality of Life (QLQ-CML24 questionnaire)
Time Frame:At screening, at each visit from Month 1 to Month 60 (if applicable) and then during the TFR phase and at STSV 30 days, assessed up to 5 years
Safety Issue:
Description:Evolution of Quality of life according to QLQ-CML24 questionnaire.
Measure:Quality of Life (QLQ-C30 questionnaire)
Time Frame:At screening, at each visit from Month 1 to Month 60 (if applicable) and then during the TFR phase and at STSV 30 days, assessed up to 5 years
Safety Issue:
Description:Evolution of Quality of life according to QLQ-C30 questionnaire.
Measure:Ponatinib pharmacokinetics (non-decisional)
Time Frame:At screening, at each visit from Month 6 (induction phase)
Safety Issue:
Description:Plasma concentrations of ponatinib over the 6 months of the induction period.
Measure:Patient' compliance to the proposed therapeutic strategy
Time Frame:At each visit during induction and consolidation phase
Safety Issue:
Description:Compliance to ponatinib and imatinib as evaluated using the Morisky medication adherence scale questionnaire

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Centre Leon Berard

Trial Keywords

  • Clinical Trial, Phase II
  • Tyrosine Kinase Inhibitors
  • Induction phase
  • Consolidation phase

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