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
Overview
- Phase
- Phase 2
- Intervention
- Ponatinib
- Conditions
- Philadelphia Chromosome Positive CML
- Sponsor
- Centre Leon Berard
- Enrollment
- 170
- Locations
- 28
- Primary Endpoint
- Impact of Ponatinib induction treatment on the TFR rate
- Status
- Active, not recruiting
- Last Updated
- 5 months ago
Overview
Brief Summary
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.
Investigators
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 3 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.
- •All EUTOS long-term survival Scores.
- •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
- •Adequate organ functions as defined below according to lab tests performed within 7 days before Day 1:
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 CYP3A
- •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.
Arms & Interventions
Induction phase with Ponatinib followed by Imatinib
Ponatinib (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)
Intervention: Ponatinib
Induction phase with Ponatinib followed by Imatinib
Ponatinib (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)
Intervention: Imatinib
Outcomes
Primary Outcomes
Impact of Ponatinib induction treatment on the TFR rate
Time Frame: 36 months after initiation of ponatinib
Rate of patients reaching a stable MR4.5 (BCR-ABL (IS) ≤0.0032% with at least 32,000 copies of ABL) for ≥ 2 years from Month 36 after initiation of ponatinib.
Secondary Outcomes
- Ponatinib pharmacokinetics (non-decisional)(At screening, at each visit from Month 6 (induction phase))
- Clinical activity of the proposed therapeutic strategy(from the date of imatinib re introduction until date of MMR or MR4.5, assessed up to 5 years)
- Incidence of Adverse Events of the proposed therapeutic strategy(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)
- Quality of Life (QLQ-CML24 questionnaire)(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)
- Quality of Life (QLQ-C30 questionnaire)(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)
- Patient' compliance to the proposed therapeutic strategy(At each visit during induction and consolidation phase)