AzTrials
AzTrials

Chronic Myeloid LeukemiaPhase 2NCT04043676

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

A Phase 2 study testing Ponatinib in people with Chronic Myeloid Leukemia, run by Fundación Teófilo Hernando, Spain at 9 sites in Spain.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
Search all trials

Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Chronic Myeloid Leukemia
What is being tested?
Ponatinib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
40 participants
Where
9 sitesSpain
Study dates
30 Apr 2019to 30 Apr 2023
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Male or female patients ≥ 18 years of age.
  • ECOG performance status of 0, 1, or 2.
  • Patient with diagnosis of BCR-ABL positive CML-CP.
  • Patient has received a minimum of 4 years of imatinib treatment, as unique TKI therapy.
  • Patient has achieved MR4 during at least 12 months with imatinib treatment, and determined by PCR lab assessment at screening.
  • Adequate end organ function.
Show all 13Show fewer
  • 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).
  • Patients must have normal marrow function
  • Patients with preexisting, well-controlled, diabetes are not excluded.
  • Have normal QTcF interval on screening ECG evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
  • Have a negative pregnancy test documented prior to enrollment
  • Be willing and able to comply with scheduled visits and study procedures.
  • Written informed consent obtained prior to any screening procedures.

Who cannot join

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

Trial locations and contacts

9 sites in 1 country.

Begonya Maestro, PhD contact

(0034) 911923700

ponazero@ifth.es

Rocio Prieto, PhD contact

(0034) 911923700

ponazero@ifth.es

9 sites in 1 country

Spain9 sites, 9 recruiting

  • Hospital Trials i Pujol

    Badalona, Barcelona, 08916

    Blanca Xicoy, Dr.

    Recruiting

  • Hospital Vall D'Hebron

    Barcelona, 08035

    Guillermo Orti, Dr.

    Recruiting

  • Hospital Universitario de Gran Canarias Dr. Negrin

    Las Palmas de Gran Canaria, 35010

    Maria Teresa Gomez, Dr.

    Recruiting

  • Hospital Unversitario de la Princesa

    Madrid, 28006

    Juan Luis Steegmann, MD PhD, jlsteegmann@gmail.com

    Recruiting

  • Hospital Universitario Ramon y Cajal

    Madrid, 28034

    Valentin Garcia Gutierrez, MD PhD, jvalentingg@gmail.com

    Recruiting

  • Hospital Universitario Doce de Octubre

    Madrid, 28041

    Rosa Ayala, MD PhD

    Recruiting

  • Hospital Regional de Malaga

    Málaga, 29010

    Antonio Jimenez, Dr.

    Recruiting

  • Hospital Universitario de Salamanca

    Salamanca, 37007

    Fermin Sanchez-Guija, MD PhD

    Recruiting

  • Hospital Clinico Universitario de Valencia

    Valencia, 46010

    Juan Carlos Hernandez Boluda, Dr.

    Recruiting

Other trials in Spain

About this study

Official title: 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.

Read the detailed description

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.

Being tested
Ponatinib
Keywords
Leukemia, BCR-ABL positive, Myeloide, Philadelphia-positive, Chronic
Medical subject headings
Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Leukemia, Bronchiolitis Obliterans Syndrome

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PonatinibDrug

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

Study groups in NCT04043676
Study groupRoleWhat they receive
Ponatinib TreatmentExperimentalPatients 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.
Receives: Drug: Ponatinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Loss MR4

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

    Measured: 96 weeks (48 weeks ponatinib consolidation phase plus 48 weeks ponatinib treatment-free remission)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Aug 2019
  2. Study start30 Apr 2019
  3. Primary completion30 Apr 2022 (estimated)
  4. Study completion30 Apr 2023 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
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).
Masking
None (open label)
Enrolment
40 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04043676
Sponsor's protocol ID
PonaZero_study
Other IDs
2017-004565-27, 2017
Status last verified
Aug 2019
First submitted
31 Jul 2019
Last updated
2 Aug 2019
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, Holyoake TL. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood. 2002 Jan 1;99(1):319-25. doi: 10.1182/blood.v99.1.319.

    PubMed 11756187

  • Hochhaus A, Masszi T, Giles FJ, Radich JP, Ross DM, Gomez Casares MT, Hellmann A, Stentoft J, Conneally E, Garcia-Gutierrez V, Gattermann N, Wiktor-Jedrzejczak W, le Coutre PD, Martino B, Saussele S, Menssen HD, Deng W, Krunic N, Bedoucha V, Saglio G. Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study. Leukemia. 2017 Jul;31(7):1525-1531. doi: 10.1038/leu.2017.63. Epub 2017 Feb 20.

    PubMed 28218239

  • Imagawa J, Tanaka H, Okada M, Nakamae H, Hino M, Murai K, Ishida Y, Kumagai T, Sato S, Ohashi K, Sakamaki H, Wakita H, Uoshima N, Nakagawa Y, Minami Y, Ogasawara M, Takeoka T, Akasaka H, Utsumi T, Uike N, Sato T, Ando S, Usuki K, Morita S, Sakamoto J, Kimura S; DADI Trial Group. Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial. Lancet Haematol. 2015 Dec;2(12):e528-35. doi: 10.1016/S2352-3026(15)00196-9. Epub 2015 Nov 10.

    PubMed 26686407

  • Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini F, Legros L, Charbonnier A, Guerci A, Varet B, Etienne G, Reiffers J, Rousselot P; Intergroupe Francais des Leucemies Myeloides Chroniques. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010 Nov;11(11):1029-35. doi: 10.1016/S1470-2045(10)70233-3. Epub 2010 Oct 19.

    PubMed 20965785

  • Mahon FX, Etienne G. Deep molecular response in chronic myeloid leukemia: the new goal of therapy? Clin Cancer Res. 2014 Jan 15;20(2):310-22. doi: 10.1158/1078-0432.CCR-13-1988. Epub 2013 Oct 28.

    PubMed 24166905

  • Mori S, Vagge E, le Coutre P, Abruzzese E, Martino B, Pungolino E, Elena C, Pierri I, Assouline S, D'Emilio A, Gozzini A, Giraldo P, Stagno F, Iurlo A, Luciani M, De Riso G, Redaelli S, Kim DW, Pirola A, Mezzatesta C, Petroccione A, Lodolo D'Oria A, Crivori P, Piazza R, Gambacorti-Passerini C. Age and dPCR can predict relapse in CML patients who discontinued imatinib: the ISAV study. Am J Hematol. 2015 Oct;90(10):910-4. doi: 10.1002/ajh.24120. Epub 2015 Sep 10.

    PubMed 26178642

  • Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT, Dang P, Goyne JM, Slader C, Filshie RJ, Mills AK, Melo JV, White DL, Grigg AP, Hughes TP. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013 Jul 25;122(4):515-22. doi: 10.1182/blood-2013-02-483750. Epub 2013 May 23.

    PubMed 23704092

  • Rousselot P, Charbonnier A, Cony-Makhoul P, Agape P, Nicolini FE, Varet B, Gardembas M, Etienne G, Rea D, Roy L, Escoffre-Barbe M, Guerci-Bresler A, Tulliez M, Prost S, Spentchian M, Cayuela JM, Reiffers J, Chomel JC, Turhan A, Guilhot J, Guilhot F, Mahon FX. Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease. J Clin Oncol. 2014 Feb 10;32(5):424-30. doi: 10.1200/JCO.2012.48.5797. Epub 2013 Dec 9.

    PubMed 24323036

  • Lee SE, Choi SY, Bang JH, Kim SH, Jang EJ, Byeun JY, Park JE, Jeon HR, Oh YJ, Kim HJ, Kim YK, Park JS, Jeong SH, Kim SH, Zang DY, Oh S, Koo DH, Kim H, Do YR, Kwak JY, Kim JA, Kim DY, Mun YC, Mauro MJ, Kim DW. Predictive factors for successful imatinib cessation in chronic myeloid leukemia patients treated with imatinib. Am J Hematol. 2013 Jun;88(6):449-54. doi: 10.1002/ajh.23427. Epub 2013 Mar 28.

    PubMed 23440689

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ponatinib in people with Chronic Myeloid Leukemia, run by Fundación Teófilo Hernando, Spain at 9 sites in Spain.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 2 Aug 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 9 sites in Spain. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Begonya Maestro, PhD ((0034) 911923700, ponazero@ifth.es), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Loss MR4 (time frame: 96 weeks (48 weeks ponatinib consolidation phase plus 48 weeks ponatinib treatment-free remission)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04043676, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Aug 2019.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in