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

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.

Inclusion Criteria:

1. Male or female patients ≥ 18 years of age.
2. ECOG performance status of 0, 1, or 2.
3. Patient with diagnosis of BCR-ABL positive CML-CP.
4. Patient has received a minimum of 4 years of imatinib treatment, as unique TKI therapy.
5. Patient has achieved MR4 during at least 12 months with imatinib treatment, and determined by PCR lab assessment at screening.
6. Adequate end organ function.
7. Patients must have the following electrolyte values ≥ LLN limits or corrected to within normal limits with supplements prior to the first dose of study medication: Potassium, Magnesium, Total calcium (corrected for serum albumin).
8. Patients must have normal marrow function
9. Patients with preexisting, well-controlled, diabetes are not excluded.
10. Have normal QTcF interval on screening ECG evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
11. Have a negative pregnancy test documented prior to enrollment
12. Be willing and able to comply with scheduled visits and study procedures.
13. Written informed consent obtained prior to any screening procedures.

Exclusion Criteria:

1. Prior AP, BC or autologous or allogenic transplant.
2. Patients with known atypical transcript.
3. CML treatment resistant mutation(s).
4. Are taking medications with a known risk of torsades de pointes (Appendix A)
5. Patient ever attempted to permanently discontinue imatinib or ponatinib treatment.
6. Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks.
7. Have clinically significant, uncontrolled, or active cardiovascular disease.
8. Have uncontrolled hypertension (diastolic blood pressure > 90 mmHg; systolic > 150 mmHg).
9. Have a history of alcohol abuse.
10. History of acute pancreatitis within 1 year prior to study entry or past medical history of chronic pancreatitis.
11. Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drug.
12. Known presence of a significant congenital or acquired bleeding disorder unrelated to cancer.
13. Have a history of another malignancy; the exception is if patients have been disease-free for at least 5 years.
14. Have undergone surgery within 14 days prior to first dose of ponatinib.
15. Treatment with other investigational within 4 weeks of Day 1.
16. Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers.
17. Patients actively receiving therapy with herbal medicines that are strong CYP3A4 inhibitors and/or inducers.
18. Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval.
19. Have an ongoing or active infection.
20. Have a known history of human immunodeficiency virus infection.
21. Have hypersensitivity to the ponatinib active substance or to any of its inactive ingredients.
22. Pregnant or nursing (lactating) women.