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Safety and effectiveness of ponatinib and asciminib in chronic myeloid leukemia patients resistant to these drugs

Verified siteRegistered drugNo placebo
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What is this trial about?

A plain-language summary of the goals, design and what participants do

The study involves patients with Chronic Myeloid Leukemia, a blood cancer that causes an overproduction of white blood cells. The treatment being tested combines two oral medicines, asciminib and ponatinib. The purpose of the study is to evaluate the proportion of patients achieving a molecular response 2 at six months.

Participants will take both tablets each day for several months while attending regular clinic visits for blood draws and bone‑marrow checks. A molecular response 2, abbreviated MR2, means the level of the genetic marker BCR::ABL1 in the blood is 1 % or lower, indicating a low amount of disease. A complete cytogenetic response, meaning no cancer‑related chromosome changes are seen in a sample of bone marrow cells, will also be assessed. Safety will be monitored by recording any adverse events, which are side effects that may range from mild to serious. The study will conclude after the final safety and effectiveness evaluations are completed.

The research process

The trial runs in 8 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Baseline assessment

    After joining the study you will have blood drawn and a bone marrow aspirate performed to confirm the current status of chronic myeloid leukemia.

    The results will be used to establish a starting point for later comparisons.

  2. Step 2

    Start combination therapy

    You will begin taking two oral medications every day.

    asciminib (asciminib hydrochloride) is taken at a total dose of 400 mg per day, usually by swallowing ten 40 mg film‑coated tablets.

    ponatinib (ponatinib) is taken at a dose of 30 mg per day, using one 30 mg film‑coated tablet.

    Both medicines are taken by mouth and can be taken with or without food.

  3. Step 3

    Daily medication routine

    Take the tablets at roughly the same time each day to keep drug levels steady.

    If you miss a dose, follow the instructions given by the study team; do not double the next dose.

  4. Step 4

    First follow‑up visit (month 3)

    Approximately three months after starting treatment you will return for a study visit.

    Blood will be drawn to measure the level of BCR::ABL1; a result of ≤10 % is called mr1.

    Your doctor will check for a complete hematologic response (normal blood counts) and record any side effects.

    If side effects are significant, the dose of one or both medicines may be reduced or temporarily stopped.

  5. Step 5

    Second follow‑up visit (month 6)

    At six months you will have another study visit.

    Blood will be tested again for BCR::ABL1; a result of ≤1 % is defined as mr2 and is the primary goal of the study.

    The study will also collect information on the highest concentration of the drugs in your blood (cmax) and the time to reach that concentration (tmax).

    Any adverse events will be documented and may lead to dose adjustments.

  6. Step 6

    Third follow‑up visit (month 12)

    At twelve months a bone marrow aspirate will be performed to look for the Philadelphia chromosome.

    The absence of this chromosome in at least 20 cells is called a complete cytogenetic response (ccr).

    Additional blood tests will assess deeper molecular responses such as mr3/mmr, mr4 and mr4.5.

    Ongoing safety monitoring continues, and dose changes may be made if needed.

  7. Step 7

    Ongoing safety monitoring

    Throughout the study you will be asked to report any new symptoms or side effects.

    The study team may schedule extra visits or laboratory tests if problems arise.

    Persistent or severe adverse events may lead to permanent discontinuation of one or both medicines.

  8. Step 8

    Study completion

    The trial is planned to continue until the end of 2030.

    If you remain on therapy without disease progression, you will continue regular assessments until the final study visit.

    The final analysis will consider overall survival, progression‑free survival, event‑free survival and the duration of response.

Who can join the trial?

9 criteria

  • You must have Chronic Myeloid Leukemia that does not respond to the medicines ponatinib or asciminib. This is called resistance and is shown by any one of the following: the disease‑specific chromosome (called Ph+) stays high, the disease‑specific gene level (BCR::ABL1) stays above set percentages, new gene mutations appear, or you lose earlier improvements such as normal blood counts (CHR), low abnormal chromosome numbers (CCyR or PCyR), or a deep molecular response (MMR).
  • You must be at least 18 years old.
  • Your overall health must allow you to perform daily activities, measured by an ECOG performance status of 0, 1, or 2 (0 = fully active, 1 = restricted but able to do light work, 2 = up and about more than half the day but unable to work).
  • Your kidneys must work well, shown by a blood test called serum creatinine that is no higher than 1.5 times the normal upper limit.
  • Your liver must work well, shown by three blood tests: total bilirubin no more than 1.5 times normal (unless you have Gilbert’s syndrome), ALT no more than 2.5 times normal (or up to 5 times if leukemia involves the liver), and AST no more than 2.5 times normal (or up to 5 times if the liver is affected).
  • Your pancreas must be normal, shown by the enzymes lipase and amylase each no higher than 1.5 times the normal limit.
  • Your heart’s electrical timing must be normal on an electrocardiogram (ECG). The corrected QT interval (QTcF) must be 450 ms or less for men and 470 ms or less for women, based on the average of three readings taken at least five minutes apart.
  • You must agree to avoid becoming pregnant or causing a pregnancy during the study. Men who could father a child must use a method that is at least 99 % effective (such as condoms with a second method) from the start of the study until six months after the last dose and must not donate sperm. Women who could become pregnant must use two reliable birth‑control methods (one with at least 99 % effectiveness and an additional barrier method) beginning at least four weeks before treatment, continue them during treatment and for six months after the last dose, have a negative pregnancy test before starting, undergo regular pregnancy testing while in the study, and must not breastfeed or donate eggs during the study and for six months after the last dose. Combined oral contraceptive pills are not allowed because they increase clot risk.
  • You must sign a written informed consent form agreeing to take part in the study.

Who cannot join the trial?

22 criteria

  • If you have previously not tolerated ponatinib or asciminib, meaning you experienced severe side effects (grade 3 or higher on the CT‑CAE grading scale) that did not improve after stopping the drug temporarily, or you had to stop the drug permanently because of intolerance.
  • If you have received any live (including weakened) vaccines, or you are expected to need such vaccines during the study.
  • If the investigator believes you are unlikely to follow the medication schedule or attend required study visits.
  • If you have used any approved tyrosine kinase inhibitors (TKIs) or experimental drugs within two weeks (or longer, depending on how long the drug stays in the body) before starting the study medication.
  • If you have any other illness that the investigator thinks would prevent full participation, could pose a significant risk to you, or would make it difficult to interpret the study results.
  • If you are unable to understand the informed consent form (ICF) or are unwilling to sign it.
  • If you have had an autologous or allogeneic stem cell transplant (SCT) less than 60 days before the first dose, or you have ongoing graft‑versus‑host disease (GVHD) or need medication to treat GVHD.
  • If you are being considered for a hematopoietic stem cell transplant (HSCT) within the next 6‑12 months.
  • If you are taking any medication that carries a known risk of Torsades de Pointes, a specific dangerous heart rhythm problem.
  • If you have active disease of the central nervous system (CNS) confirmed by laboratory tests, or you have severe uncontrolled medical problems such as uncontrolled diabetes, an active infection, or pulmonary hypertension (high blood pressure in the lungs).
  • If you have significant heart or blood‑vessel disease, including any history of myocardial infarction (heart attack), unstable angina (chest pain), cerebrovascular accident (stroke) or transient ischemic attack (TIA), blockages in peripheral vessels, any procedure to open vessels (such as a stent), congestive heart failure (CHF) classified as NYHA class III or IV within the past 6 months, a low left ventricular ejection fraction (LVEF) (below the normal range) within 6 months, serious irregular heartbeats (atrial or ventricular arrhythmias), or blood clots in veins or lungs (deep venous thrombosis or pulmonary embolism) within the past 6 months.
  • If you have a significant bleeding disorder that is not related to your leukemia.
  • If you have uncontrolled high blood pressure (systolic > 150 mmHg or diastolic > 90 mmHg). Blood pressure must be controlled before entering the study.
  • If you have poorly controlled diabetes, defined as HbA1c values above 7.5 % (59 mmol/mol) on three or more occasions in the past year.
  • If you are taking strong CYP3A inhibitors or inducers, which can change how the study drugs are processed in the body.
  • If you have a documented history of alcohol abuse.
  • If you have had an episode of acute pancreatitis within the past year or have chronic pancreatitis.
  • If you have a malabsorption syndrome or other serious gastrointestinal illness that could affect oral absorption of the study medication.
  • If you have a history of another cancer, except for cervical cancer in situ, basal cell carcinoma, or squamous cell skin cancer, unless you have been cancer‑free for at least five years.
  • If you are known to be hypersensitive (allergic) or have had a severe reaction to ponatinib or any of its inactive ingredients.
  • If you are known to be hypersensitive (allergic) or have had a severe reaction to asciminib or any of its inactive ingredients.
  • If you are a female who is pregnant or currently breastfeeding.
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Investigated drugs

  • Scemblix

    is an oral tablet that contains the medicine asciminib. It works by blocking a specific part of the protein that drives the growth of chronic myeloid leukemia cells. In this trial, patients take Scemblix together with another drug to see if the combination can better control the disease, especially in people whose leukemia has not responded well to other treatments.

  • Iclusig

    is an oral tablet that contains the medicine ponatinib. Ponatinib blocks the activity of a protein called BCR‑ABL, which is responsible for the uncontrolled growth of leukemia cells. In the study, Iclusig is given alongside Scemblix to test whether the two drugs together can improve the molecular response in patients whose leukemia is resistant to one or both medicines when used alone.

What is already known about the treatment

  • Asciminib

    This medication is taken as a film‑coated tablet swallowed by mouth. It is an approved drug for chronic myeloid leukemia and is described in recent medical literature as a newer targeted therapy. Asciminib works by attaching to a special pocket on the BCR‑ABL protein, stopping the protein from sending growth signals to cancer cells. It belongs to the class of BCR‑ABL inhibitors, often called targeted cancer medicines.

  • Ponatinib

    This drug is also given as a film‑coated tablet for oral use. Ponatinib is an approved treatment for chronic myeloid leukemia, especially when patients do not respond to other medicines, and has extensive data in the medical literature. It blocks the BCR‑ABL protein, including a common resistant form, by fitting into the protein’s active site and halting its activity. Ponatinib is classified as a tyrosine‑kinase inhibitor used in cancer therapy.

Investigated diseases

Chronic Myeloid Leukemia - Chronic Myeloid Leukemia (CML) is a blood cancer that begins in the bone marrow and causes an excess of white blood cells. It typically starts in a chronic phase where symptoms are mild or absent. Over time the disease can shift to an accelerated phase with rising blood counts and worsening fatigue. If it continues, it may progress to a blast phase, which is marked by many immature cells in the blood. The progression is driven by a genetic abnormality known as the Philadelphia chromosome.
Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IITrial ID2025-521126-15-00Protocol codePONTHIACEstimated enrolment30 patientsSponsorGrupo Espanol De Leucemia Mieloide Cronica (GELMC)

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