Accepts Healthy Volunteers
Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms
An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.
An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.
Searching Both is inclusive of interventional and observational studies.
|Eligible Ages||18 Years and Over|
This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.
Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.
Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.
Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.
Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.
The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.
|Fundación Teófilo Hernando, Spain|
The person who is responsible for the scientific and technical direction of the entire clinical study.
|Juan Luis Steegmann, MD PhDValentin Garcia Gutierrez, MD PhDRosa Ayala, MD PhDLuis Felipe Casado, Dr.Fermin Sanchez-Guijo, MD PhDJuan Carlos Hernandez, Dr.Guillermo Orti, Dr.Blanca Xicoy, Dr.Antonio Jimenez, Dr.Maria Teresa Gomez, Dr.|
|Principal Investigator Affiliation||Fundación de Investigación Biomédica - Hospital Universitario de La PrincesaHospital Universitario Ramon y CajalHospital Universitario Doce de OctubreHospital Universitario Virgen del RocioUniversity of SalamancaHospital Clínico Universitario de ValenciaHospital Vall d'HebronHospital German Trials i PujolHospital Regional Universitario de MalagaHospital Universitario de Gran Canarias Dr. Negrin|
Category of organization(s) involved as sponsor (and collaborator) supporting the trial.
The disease, disorder, syndrome, illness, or injury that is being studied.
|Chronic Myeloid Leukemia|
One decade ago, it was thought that cessation of Tyrosine Kinase Inhibitor (TKI) treatment in chronic myeloid leukemia in chronic phase (CML-CP) patients could be ineluctably followed by relapse, even in the setting of a complete molecular response. This paradigm was mainly based on two facts: the absence of the known graft vs.#46;leukemia effect of bone marrow transplant, and the demonstration that quiescent stem cells were resistant to TKI. Until then, the standard of care was to treat CML-CP patients indefinitely with TKI. The potential medical benefits of successful cessation include minimization of drug-drug interactions, elimination of chronic side effects, and pregnancy without exposure to TKIs. Hence, physicians, as well as patients, have shown a strong interest to explore cessation strategies for BCR-ABL inhibitors. This paradigm of treating CML-CP patients with TKIs indefinitely was broken by the French "Stop imatinib study" (STIM), which investigated the feasibility of imatinib cessation in a highly selected group of patients who achieved and maintained complete molecular response (CMR) defined as undetectable BCR-ABL levels with high sample sensitivity (10-5 or greater) for a minimum of 2 years. With a median follow up of 30 months, 39% of patients have successfully stopped imatinib therapy. This provided the first evidence that achieving and maintaining deep molecular responses is a pre-requisite for successful therapy cessation. Since the seminal study of the French Group, led by Mahon and Reiffers, multiple trials have studied the potential role of discontinuation of imatinib to achieve a stable TFR. Most of them required the absence of undetectable BCR-ABL to include the patient in the given study. In fact, the largest study of discontinuation, the EURO-SKI, and the ISAV study require a response MR4 or better to be eligible. Definition of relapse has also varied. In earlier studies, it was more stringent, and the trigger for reinitiating the treatment was the detection of the transcript. However, other studies have set the definition of relapse as the loss of major molecular response (MMR). The larger study in course, the EURO-SKI, has also defined the relapse as the loss of major molecular response. Taking all the studies together, the median probability of TFR by 2 years is 51%. The experience is similar with patients treated with nilotinib upfront. The ENESTfreedom trial included 215 patients treated frontline with nilotinib having obtained a MR4.5, and receiving afterwards a consolidation phase with nilotinib 600 mg per day during one year. After this phase, those patients with stable MR4.5 discontinued the therapy. The results showed that the probability of TFR by 48 weeks was 51.6%. Other trials have explored the possibility of a consolidation therapy with second-generation TKIs (2GTKI) in patients previously treated with imatinib. Some years ago, the ENESTcmr trial has shown that in patients not having achieved MR4.5, twice as many patients randomized to nilotinib vs.#46; imatinib achieved MR4.5 after 12 months of treatment, allowing them to be eligible for discontinuation trials. The rational of the ENESTop trial lies in this previous experience and explains its design: patients treated previously with imatinib, and having obtained a MR4.5 with nilotinib in second line, received a consolidation with nilotinib during 1 or 2 years, and then if the MR4.5 was stable, were eligible to discontinue therapy. With this strategy, the probability of TFR by 48 weeks was 58%. A similar approach has been followed by the Japanese investigators, but with patients having treated with dasatinib in second line. The probability of TFR by 2 years after discontinuation was 48%. Response of Rescue Therapy after Relapse Patients after relapse were treated again, most of them with the TKI they received previous discontinuation. In the STIM study, in terms of regaining molecular response, 61 patients had a molecular recurrence, 56 regained undetectable BCR-ABL transcript level after a median of 4 months on imatinib (range 0-21 months). Five patients did not return to undetectable transcript level: four remained treatment-free with detectable transcript (range 0.05% to 0.3%) and one patient was switched to dasatinib due to loss of Complete Cytogenetic Response (CCyR). No loss of hematological response or progression to advanced phase was noted after stopping imatinib. Similar results were observed in another study with a median 33 months of follow-up, and 55% of patients that met the protocol definition of molecular relapse (BCR-ABL detected by RT-qPCR in two consecutive tests). Twenty-one of 22 patients who restarted imatinib regained undetectable BCR-ABL transcript level. One patient remained in MMR at the 14-month follow-up. Taking studies altogether the probability of regaining MMR is almost 100%, and the probability of regaining CMR ranges from 89%. The rationale for the Study Design Ponatinib has shown to induce deeper molecular responses compared with imatinib. Therefore, ponatinib treatment could increase the proportion of patients who could discontinue treatment successfully. This strategy that includes treatment change to a more powerful treatment before treatment discontinuation has not been evaluated in any of the previous clinical trials, and will be explored in the current study. In this framework, the purpose is to determine the rate of successful TFR within the first 48 weeks following cessation of treatment in patients who achieved MR4 on imatinib and maintained MR4 on ponatinib after a switch from imatinib. Eligible patients have been previously treated with imatinib as unique tyrosine kinase inhibitor (at least 4 years) and have documented MR4 (at least 12 months) at the time of switch to ponatinib to study entry.
Experimental: Ponatinib Treatment
Patients will be treated with 15 mg/day of ponatinib during 48 weeks. If a patient maintains MR4 throughout the 48 weeks, he/she will be eligible to start the ponatinib TFR phase. If a patient has confirmed loss of MR4 (two consecutive BCR-ABL > 0.01% IS) or loss of MMR (no confirmation needed), he/she will not be eligible for the TFR phase. Instead, he/she will restart imatinib treatment.
Drug: - Ponatinib
All patient will take 15 mg/day ponatinib oral during 48 weeks.
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