Neoplasms

Blood and Lymph Conditions

All Conditions

Symptoms and General Pathology

Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Neoplasms by Histologic Type

Hematologic Diseases

Myeloproliferative Disorders

Bone Marrow Diseases

Chronic Disease

Disease Attributes

Myeloid Leukemia

Chronic Graft Versus Host Disease

Chronic Myeloid Leukemia

Chronic Myeloproliferative Disorders

Antineoplastic Agents

All Drugs and Chemicals

Amino Acids

Ponatinib

Imatinib Mesylate

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

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.

All patient will take 15 mg/day ponatinib oral during 48 weeks.

Begonya Maestro, PhD

Rocio Prieto, PhD

Blanca Xicoy, Dr.

Guillermo Orti, Dr.

Maria Teresa Gomez, Dr.

Juan Luis Steegmann, MD PhD

Valentin Garcia Gutierrez, MD PhD

Rosa Ayala, MD PhD

Antonio Jimenez, Dr.

Fermin Sanchez-Guija, MD PhD

Juan Carlos Hernandez Boluda, Dr.

Luis Felipe Casado, Dr.

Fermin Sanchez-Guijo, MD PhD

Juan Carlos Hernandez, Dr.

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 treatment-free remission (TFR) within the first 48 weeks following cessation of treatment in patients who achieved Molecular Response 4 (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.

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 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. 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.

40 patients of both genders with chronic myeloid leukemia in MR4. Each patient will enter in the ponatinib consolidation phase (48 weeks) and them in the ponatinib treatment-free remission (96 weeks).

This is a single-arm, open label study designed to determine the rate of successful treatment free remission (TFR) in patients who achieved and maintained molecular response 4 (MR4) on ponatinib. This study has 2 main phases: ponatinib consolidation (48 weeks), and ponatinib TFR phases (96 weeks). All patients who have received a minimum of 4 years of imatinib therapy as unique TKI therapy, he/she has documented MR4 at least 12 months for study entry, and he/she shall continue with MR4 before the discontinuation of the ponatinib treatment.

Consolidation Treatment With Ponatinib 15 mg on Treatment Free-Remission Rate in Patients With Chronic Myeloid Leukemia

Multicenter, Open-Label, Single Arm, Phase II Exploratory Study to Evaluate the Effect of a One-Year Consolidation Treatment With Ponatinib 15 mg on Treatment Free-Remission Rate in Patients With Philadelphia-Positive Chronic Myeloid Leukemia, Who Had Previously Achieved a Deep Molecular Response With Imatinib

Proportion of patients without confirmed loss of MR4 or loss of MMR (don't require confirmation) within 48 weeks following ponatinib therapy cessation.

Fundación Teófilo Hernando, Spain

Spots Global Cancer Trial Database for myeloide

Every month we try and update this database with for myeloide cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for myeloide

Every month we try and update this database with for myeloide cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for myeloide cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.