Trial document




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  DRKS00016363

Trial Description

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Title

With Ponatinib on the track for treatment-free-remission in chronic myeloid leukaemia

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Trial Acronym

Pontrack

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URL of the Trial

https://www.uniklinikum-jena.de/cml/cml_allianz_studieninformation.html

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Brief Summary in Lay Language

Until about ten years ago, it was thought that the drugs for the treatment of chronic myeloid leukemia (CML), tyrosine kinase inhibitors (TKI) must be taken lifelong in order to control the disease. In recent years, however, in clinical studies worldwide several thousand patients, in whom the therapy worked very well and therefore a residual disease was not or hardly detectable, the TKI discontinued. About half of the patients were able to remain therapy-free.
The evaluations of these discontinuation studies have shown that, above all, longer-lasting, deep response to therapy (molecular response according to the international scale of MR4 or better = equal to or less than 0.01% BCR-ABL) increases after a controlled discontinuation of TKI the chances to stay therapy-free.
Treated with the highly potent TKIs nilotinib, dasatinib or bosutinib, deep molecular response is usually achieved within a year. Patients who not achieved a deep molecular response after 3 years or who not stable keep it may have a poorer chance of achieving this therapeutic goal if they continue treatment with these TKIs. This affects about 20-30% of all CML patients. In order to give patients with a response between 0.5-0.01 BCR-ABLIS the perspective of a therapy-free life, the Pontrack study was developed. In this study, the TKI ponatinib is used.
Ponatinib (trade name Iclusig ©) is a highly potent 3rd generation TKI. In Germany, ponatinib is approved for the treatment of CML patients who do not benefit from other TKI therapy due to resistance or intolerance. Comparative evaluations of results from various clinical trials shows that ponatinib appears to be even more effective than nilotinib, dasatinib or bosutinib.
Within the Pontrack study the patient will start with a dose of 30 mg / day. The dose may be reduced to 15 mg or increased up to 45 mg, depending on response. The aim is to achieve a deep molecular response in preparation for TKI discontinuation (outside the Pontrack study). Study participation ends after 2 years, regardless of the therapy response achieved so far.
In previous studies, ponatinib showed an increased risk of cardiovascular events. These risks are addressed in the Pontrack study a) by exclusion of patients with corresponding pre-existing conditions and therefore increased risk b) close and often monitoring of cardiovascular functions before and during the study and c) the lowest possible dosage of the study drug. If side effects occur, the dosage of ponatinib may be reduced or treatment may be discontinued until the adverse events resolved.
Before and during study treatment, you must consult your study physician regularly to monitor your health and to determine the response. During these visits, cardiovascular functions were controlled by blood tests, ECGs, ultrasound and other physical examinations. A total of 13 visits in the study cente are scheduled. In addition, within the first three months blood testing performed by your family doctor are scheduled every 2 weeks.

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Brief Summary in Scientific Language

There is a reasonable chance for a CML patient in deep molecular remission (DMR, defined as stable BCR-ABL ≤ 0,01% or MR4 according international Scale , repectively) and specific preconditions to be treatment-free. Approximately 50% of patients remained therapy-free after TKI discontinuation.
Among the preconditions that can serve as guidance for stopping TKI, DMR duration was the most important factor. By successful stopping, a considerable proportion of patients will be spared from treatment-induced side effects and a noticeable amount of health expenditure saved.
However, there is a substantial proportion of patients who do not achieve MR4 during their treatment course. E.g., under nilotinib 65.6% of patients achieved MR4 by 5 year. The incidence curve slows down after 3-4 years (rate after 3 years: 50%).
Ponatinib is a third generation TKI, which has shown to be high effective in both early and advanced phases of CML and those bearing resistant mutations, specifically T315I.
In the largest cohort of chronic phase CML patients on third-line TKI therapy, Khan et al. found that ponatinib is associated with significantly better OS than any other TKI used as third-line therapy.
On the other hand, a higher proportion of serious adverse events, especially arterial thrombosis and cardiovascular events were observed under ponatinib therapy.
Therefore, the selection of patients for such a trial has to be carried out very carefully. Key factors are conventional cardiovascular risk factors, like age, diabetes mellitus, or hypertension; molecular risk factors such as age-related clonal (somatically mutated) hematopoiesis; and pre-existing cardiovascular co-morbidities. In this study, patients suffering of comorbidities increasing the risk of VAE will be not be included and the risk can be minimized.
As significant associations between dose intensity and risk of arterial occlusive events were demonstrated, we propose to treat patients with a minimum of two years with ponatinib 30 mg as starting dosage in order to reduce risks of AOE but to have substantial efficacy. Dose reduction to 15 mg will be permitted, if patients reach MR4, dose increase to the standard dose of 45 mg is allowed for patients not reaching MR4 after 12 months.
All patient will be examined before and closed monitored during study treatment
The main study endpoint is the proportion of patients reaching an MR4 after 2 years of treatment.
In line with data of the ENESTCMR study, the hypothesis is that at least 20% of patients will gain an MR4 (in patients without treatment change the chance is only about 5-10 % after 2 years). To test this hypothesis, 48 patients should be evaluable.
In a post-study register/follow-up the success of stopping treatment after this ponatinib treating phase will be evaluated.

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Do you plan to share individual participant data with other researchers?

No

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Description IPD sharing plan:

[---]*

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Organizational Data

  •   DRKS00016363
  •   2019/12/19
  •   [---]*
  •   yes
  •   Approved
  •   2019-006F-1246, Medizinische Ethik-Kommission II Medizinische Fakultät Mannheim der Universität Heidelberg
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Secondary IDs

  •   U1111-1240-5511 
  •   2018-004564-59 
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Health Condition or Problem studied

  •   C92.11 -  [generalization C92.1: Chronic myeloid leukaemia [CML], BCR/ABL-positive]
  •   10009013
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Interventions/Observational Groups

  •   Ponatinib 30 mg/d for 24 months. Dose reduction to 15 mg will be permitted, if patients reach a deep molecular Remission (MR4 or better), dose increase to the standard dose of 45 mg is allowed for patients not reaching MR4 after 12 months until MR4 is reached.
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Characteristics

  •   Interventional
  •   [---]*
  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Treatment
  •   Single (group)
  •   III
  •   Yes
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Primary Outcome

Proportion of patients achieving MR4 after two years of treatment with ponatinib.

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Secondary Outcome

• Molecular status (no MMR, MMR, MR4, and MR4.5) at the evaluation times defined in the visit schedule
• Time from inclusion to first MR4 and to first MR4.5
• Assessment of safety profile, tolerability and adverse events under ponatinib treatment
• Assessment of health-related quality of life (QoL) profiles under ponatinib treatment (as measured by the EORTC QLQ-C30 and CML 24)
• Identification of clinical and biological factors associated with the achievement of MR4 or better under ponatinib (e.g. risk scores (Sokal/Euro/EUTOS/ELTS), gender, duration of TKI treatment, molecular level at study entry)
• Evaluation of medico-economic impact of ponatinib therapy with the possibility of a TFR approach
• Evaluation of overall survival and progression-free survival

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
  • University Medical Center 
  • Doctor's Practice 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
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Recruitment

  •   Actual
  •   2019/12/20
  •   60
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

• Female or male ≥ 18 years of age
• Patients with CML in chronic phase (CP)
• BCR-ABLIS between 0,5-0,01 and demonstrated by the last PCR before inclusion
• not achieving MR4 (defined as < 0,01% BCR-ABLIS) or not achieving a stable MR4 (defined as no continuous in MR4 during the last 12 months before inclusion) after ≥ 3 years of treatment with nilotinib, dasatinib and / or bosutinib in first or second line
• Philadelphia -chromosome and/or BCR-ABL (either b3a2 and /or b2a2) fusion gene positive CML
• Patients must have had an eye examination including fundoscopy by an ophthalmologist within 8 weeks prior to first treatment

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Exclusion Criteria

Subjects presenting with any of the following criteria will not be included in the trial:
 Failure of any TKI at any time during CML treatment according to current ELN criteria (including any detection of mutations or additional cytogenetic aberrations)
 Prior diagnosis of accelerated phase (AP) or blast phase (BP) at any time in the history of the disease
 Previously planned or performed allogenic SCT
 At time of inclusion (results of screening)
• High cardiac risk according to ESC score (≥ 10%)
• Clinically significant resting bradycardia (<50 bpm)
• QTcF interval on baseline electrocardiogram (ECG) evaluation, defined as QTcF of >450 ms in males or > 470 ms in females.
• Treatment with inhibitors of CYP3A4 or medications that have been well documented to prolong the QT interval (see chapter V.4.5)
• Uncontrolled hypertension (diastolic blood pressure ≥ 90 mm Hg; systolic ≥ 140 mm Hg). Patients with hypertension should be under treatment on study entry to effect blood pressure control
• Ankle-brachial-index (ABI) < 0,9 or >1,4 or alternatively signs of arterial occlusion in duplex sonography
• No adequate hepatic function
(total serum bilirubin > 1.5 × ULN, unless due to Gilbert’s syndrome; Alanine aminotransferase (ALAT) > 2.5 × ULN,
or > 5 × ULN if leukemic infiltration of the liver is present; aspartate aminotransferase (ASAT) > 2.5 × ULN,
or > 5 × ULN if leukemic infiltration of the liver is present)
• Positive hepatitis B virus serology test
• No adequate pancreatic function
(serum lipase and amylase >1.5 × ULN)
• No adequate renal function [estimated creatinine clearance (eGFR) of < 50 ml/min, Cockcroft and Gault Score]
• Other severe or uncontrolled medical conditions(e.g. Infection)
• Women who are pregnant or breast feeding
• positive serum pregnancy test (of woman with childbearing potential, see page 59)
• woman of childbearing potential not agreeing to use an higly-effective form of contraception or fertile male not agreeing to use an acceptable birth control method (for definition see appendix) with sexual partners throughout study participation until 90 days after EoT.
• Legally incapacitated
• No ability to comprehend and sign the informed consent.
• Held in an institution by legal or official order
• Not able to take oral therapy
• No willingness or ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
• Participation in other clinical trials

 History of
• myocardial infarction (MI)
• clinically significant (as determined by the treating physician) atrial or ventricular arrhythmias
• coronary heart disease
• congenital long QT syndrome or family history of
• use of a ventricular paced pacemaker
• other clinically significant heart disease (e.g. unstable angina, congestive heart failure) or impaired cardiac function
• hyperlipidaemia.
• cerebrovascular accident (CVA, e.g. stroke) or transient ischemic attack (TIA)
• peripheral vascular infarction, including visceral infarction or other vascular occlusive events
• any revascularization procedure, (e.g. placement of stents, bypasses)
• venous thromboembolism, including deep venous thrombosis or pulmonary embolism, within 6 months prior to enrolment
• retinal venous occlusions
• Moderate or severe acute or chronic liver disease
• alcohol abuse.
• severe hypertriglyceridemia
• either acute pancreatitis within 1 year before study entry or chronic pancreatitis
• renal artery stenosis
• moderate , severe or end-stage chronic renal disease unrelated to tumor
• severe diabetes with end organ damage (e.g. microalbuminuria) or poorly controlled diabetes, defined as HbA1c values over the previous year of > 7.5% (59 mmol/mol) on more than 3 occasions. Patients with pre-existing, well-controlled diabetes are not excluded.
• bleeding issues
• any other malignancy except if neither clinically significant nor requires active intervention.

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Addresses

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    • Universität Heidelberg
    • Seminarstr. 2
    • 69115  Heidelberg
    • Germany
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    •   [---]*
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    • Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie (IBE) der Ludwig-Maximilians-Universität München
    • Mr.  PD Dr. rer. biol. hum.  Markus  Pfirrmann 
    • Marchioninistr. 15
    • 81377  München
    • Germany
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    • Medizinische Fakultät Mannheim, Universität Heidelberg, III. Medizinische Klinik, MCC Studienzentrale
    • Ms.  Prof. Dr. med.  Susanne  Saußele 
    • Theodor-Kutzer-Ufer 1-3
    • 68167  Mannheim
    • Germany
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    • Medizinische Fakultät Mannheim, III. Medizinische Klinik, MCC-Studienzentrale
    • Ms.  Prof. Dr. med.  Susanne  Saußele 
    • Theodor-Kutzer-Ufer 1-3
    • 68167  Mannheim
    • Germany
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Sources of Monetary or Material Support

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    • Incyte Biosciences International Sàrl
    • Route de la Corniche 1
    • 1066  Epalinges
    • Switzerland
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    •   +49 151/11552502
    •   [---]*
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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

  •   Ethikvotum
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* This entry means the parameter is not applicable or has not been set.