Safety and Efficacy of Ponatinib Plus Asciminib Combination in Chronic Myeloid Leukemia Patients with Resistance to Ponatinib and/or Asciminib
- Trial ID
- 2025-521126-15-00
- Protocol
- PONTHIAC
Trial statistics
Diseases & Conditions
Objectives
The primary objective is to assess the proportion of patients with Chronic Myeloid Leukemia achieving a molecular response 2 (MR2) after six months of combined asciminib and ponatinib therapy, reflecting early molecular efficacy that correlates with long‑term disease control. Secondary objectives include:
- Characterization of pharmacokinetic parameters for the asciminib‑ponatinib combination.
- Determination of the proportion of patients attaining a complete cytogenetic response (CCyR) at six months.
- Evaluation of the overall safety and tolerability profile of the combination regimen.
- Assessment of cytogenetic response rates at twelve months.
- Measurement of molecular response rates across defined thresholds.
- Estimation of hematologic response rates.
- Quantification of treatment discontinuations attributable to adverse events.
- Documentation of dose reductions and interruptions caused by adverse events.
- Analysis of duration of response (DoR) and time to response (TTR).
- Characterization of progression rates to accelerated or blast phase disease.
- Calculation of progression‑free survival, event‑free survival, and overall survival.
Participants
The trial enrolled adult participants (≥ 18 years) of both sexes diagnosed with Chronic Myeloid Leukemia that was resistant to ponatinib and/or asciminib, as defined by specific cytogenetic or molecular criteria after prior tyrosine‑kinase inhibitor therapy. Eligible individuals were required to have an Eastern Cooperative Oncology Group performance status of 0–2, adequate renal, hepatic, pancreatic function, and a normal QTcF interval (≤ 450 ms in males, ≤ 470 ms in females). Contraception requirements were applied to participants of reproductive potential, and all participants provided written informed consent. The sponsor did not provide information on the total number of enrolled subjects.
Plans and Procedures
The interventional Phase 4 study evaluates the safety and efficacy of the oral combination of ponatinib (Iclusig 45 mg film‑coated tablet) and asciminib (Scemblix 20 mg or 40 mg film‑coated tablets) in adult patients with Chronic Myeloid Leukemia who are resistant to either agent. Eligible participants must be ≥18 years old, have an ECOG performance status of 0–2, meet defined renal, hepatic, pancreatic, and cardiac laboratory criteria, and provide written informed consent. After a screening visit to confirm eligibility, the baseline (Day 1) visit initiates the combined therapy. Subsequent study visits are scheduled at Week 4, Month 3, Month 6, Month 12, and an end‑of‑study visit, during which molecular response (MR2), cytogenetic response, hematologic response, pharmacokinetic parameters (Cmax, Tmax), and adverse events are assessed. The primary endpoint is the proportion of patients achieving MR2 (≤1 % BCR::ABL1) at 6 months; secondary endpoints include response milestones at 3‑month intervals, complete cytogenetic response at 6 and 12 months, progression‑free survival, event‑free survival, overall survival, and safety outcomes. Participant involvement extends for up to 12 months of treatment plus the final assessment, with the overall trial recruitment period spanning from August 2026 to December 2030. Early termination may occur due to unacceptable toxicity, disease progression to accelerated or blast phase, withdrawal of consent, or failure to comply with protocol‑required assessments.
Treatment
The investigational regimen includes asciminib hydrochloride supplied as Scemblix film‑coated tablets. Two tablet strengths are utilized: 40 mg tablets and 20 mg tablets, both administered orally. Each administered dose corresponds to a total of 400 mg of asciminib hydrochloride per dosing event, with the tablet strength selected to achieve the prescribed total dose.
In addition, the study incorporates ponatinib provided as Iclusig 45 mg film‑coated tablets. The medication is taken orally, with each dose delivering 30 mg of ponatinib. The tablet strength is fixed, and the dosing amount is defined by the protocol.
No additional non‑experimental therapies, such as standard‑of‑care agents, placebo, or other comparator treatments, are administered as part of the study protocol.
Efficacy
Efficacy will be evaluated using molecular, cytogenetic, and hematologic response criteria as well as time‑to‑event endpoints. The primary efficacy parameter is the proportion of subjects achieving MR2, defined as ≤ 1 % BCR::ABL1 transcript level at 6 months, measured by quantitative reverse transcription PCR (qRT‑PCR) on peripheral blood samples. Secondary efficacy parameters include pharmacokinetic measures (Cmax and Tmax), complete cytogenetic response (CCyR) assessed by metaphase analysis of bone marrow aspirates (absence of the Philadelphia chromosome in ≥ 20 cells) at 6 months and 12 months, complete hematologic response (CHR) at 3 months, and molecular response levels (MR1, MR2, MR3/MMR, MR4, MR4.5) evaluated at 3‑month intervals.
Additional efficacy assessments comprise duration of response, time to response (TTR), progression‑free survival (PFS), event‑free survival (EFS), overall survival (OS), and rates of disease progression to accelerated or blast phase. These time‑to‑event endpoints are calculated from the date of first dose of the combination therapy to the respective clinical event.
All molecular assessments will employ validated qRT‑PCR assays with standardized conversion to the International Scale. Cytogenetic evaluations will be performed on bone marrow specimens using conventional karyotyping. Hematologic response will be determined by complete blood count parameters according to established criteria. Data collection is scheduled at baseline, every 3 months for molecular response, at 6 months and 12 months for cytogenetic response, and continuously for safety and survival outcomes throughout the study period.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Diagnosed patients with CML resistant to ponatinib and/or asciminib. Resistance to prior TKI therapy is defined as follows (patients must meet at least 1 criterion): a) Three months after the initiation of prior TKI therapy: No cytogenetic response (> 95% Ph+) or failure to achieve CHR or new mutation. b) Three months after the initiation of prior TKI therapy: BCR::ABL1BCR::ABL1 >10% and/or Ph+ >65% or new mutation. c) Six months after the initiation of prior TKI therapy: BCR::ABL1 >1% and/or Ph+ >35% or new mutation. d) At any time after the initiation of prior TKI therapy, development of new BCR::ABL1 kinase domain mutations in the absence of CCyR or PCyR. e) At any time after the initiation of prior TKI therapy, development of new clonal evolution in the absence of CCyR or PCyR. f) At any time after the initiation of prior TKI therapy, loss of CHR, loss of CCyR or PCyR, or the confirmed loss of MMR in 2 consecutive tests, one of which has a BCR::ABL1 BCR::ABL1 transcript level of ≥1% or new mutation.
- Patients ≥ 18 years old.
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
- Have adequate renal function as defined by the following criterion: serum creatinine ≤ 1.5 × upper limit of normal (ULN).
- Have adequate hepatic function. a) Total serum bilirubin ≤ 1.5 × ULN, unless due to Gilbert’s syndrome. b) Alanine aminotransferase (ALT) ≤ 2.5 × ULN, or ≤ 5 × ULN if leukemic infiltration of the liver is present. c) Aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN if leukemic infiltration of the liver is present.
- Have normal pancreatic status as defined by the following criterion: Serum lipase and amylase ≤ 1.5 × ULN.
- Have normal QT interval corrected (Frederica) (QTcF) interval on screening electrocardiogram (ECG) evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470ms in females. For this criteria the average of 3 ECG’s conducted at least 5 minutes apart.
- Willingness to avoid pregnancy or fathering children based on the criteria below. a) Male participants with reproductive potential must agree to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through 180 days (6 months) after the last dose of study treatment, even if they have undergone a successful vasectomy, and must refrain from donating sperm during this period. Permitted methods that are at least 99% effective in preventing pregnancy should be communicated to the participants and their understanding confirmed. b) WOCBP participants: i) Must commit either to abstain continuously from heterosexual sexual intercourse or agree to take appropriate precautions to avoid pregnancy (by using 2 different methods of birth control: one with at least 99% certainty and an additional effective [barrier] method) starting at least 4 weeks before taking the study treatment, while taking the study treatment, during breaks (dose interruptions), and for at least 180 days (6 months) after stopping the study treatment. Permitted methods that are at least 99% effective in preventing pregnancy and the permitted additional effective (barrier) methods should be communicated to the participants and their understanding confirmed. Note: Because of the increased risk of venous thromboembolism, combined oral contraceptive pills are not recommended. If a participant is currently using combined oral contraception, the participant should switch to other effective methods. The risk of venous thromboembolism continues for 4 to 6 weeks after discontinuing combined oral contraception. ii) Must have a negative serum pregnancy test at screening (within 10-14 days of the first study drug treatment) and before the first dose on Day 1 (within 24 hours of initiating treatment). iii) Agree to ongoing pregnancy testing during the course of the study; weekly during the first month of study drug treatment, then monthly thereafter for women with regular menstrual cycles or every 2 weeks for women with irregular menstrual cycles (even if true abstinence is the chosen method of birth control) up to and including the EOT visit. iv) Must refrain from breastfeeding and donating oocytes during the course of study and for 180 days (6 months) after the last dose of study treatment. v) A female participant who is not considered to be of childbearing potential as defined in Appendix A is eligible. Note: The participants should be informed about the option of donation and cryopreservation of germ cells before the study if applicable.
- Provide written informed consent.
Exclusion Criteria
- Previous intolerance to ponatinib or asciminib defined as: a) Previous CT-CAE > or =3 not resolved after temporary discontinuation of the drug. b) Discontinuation of treatment due to permanent intolerance according to investigator judgment. c) Adverse effect that required permanent discontinuation.
- Have a significant bleeding disorder unrelated to CML.
- Have a history of alcohol abuse according to medical records.
- Have a history of either acute pancreatitis within 1 year of study or chronic pancreatitis.
- Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drug.
- Have a history of another malignancy, other than cervical cancer in situ or basal cell or squamous cell carcinoma of the skin; the exception is if patients have been disease-free for at least 5 years.
- Known hypersensitivity or severe reaction to ponatinib or excipients of ponatinib.
- Known hypersensitivity or severe reaction to ascinimib or excipients of ascinimib.
- Females who are pregnant or lactating.
- Receipt of live (including attenuated) vaccines or anticipation of need for such vaccines during the study.
- Inability or unlikeliness to comply with the dose schedule and study evaluations, in the opinion of the investigator.
- Have used any approved TKIs or investigational agents within 2 weeks or half-lives of the agent, whichever is longer, prior to receiving study drug.
- Any condition or illness that would, in the investigator's judgment, interfere with full participation in the study, including administration of study drug and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.
- Inability of the participant (or guardian, or legally authorized representative) to comprehend the ICF or unwillingness to sign the ICF.
- Have undergone autologous or allogeneic stem cell transplant (SCT) < 60 days prior to receiving the first dose of ponatinib or have any evidence of ongoing graft versus-host disease (GVHD) or GVHD requiring immunosuppressive therapy.
- Are being considered for hematopoietic SCT (HSCT) within 6-12 months of enrollment (note: ponatinib is not to be used as a bridge to HSCT in this trial)
- Are taking medications with a known risk of Torsades de Pointes.
- Have active central nervous system (CNS) disease as evidenced by cytology or pathology; in the absence of clinical CNS disease, lumbar puncture is not required. Patient with severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol (e.g. uncontrolled diabetes, active or uncontrolled infection, pulmonary hypertension) will be excluded.
- Have clinically significant, uncontrolled, or active cardiovascular disease, specifically including, but not restricted to: a) Any history of myocardial infarction (MI), unstable angina, cerebrovascular accident, or transient ischemic attack (TIA). b) Any history of peripheral vascular infarction, including visceral infarction. c) Any revascularization procedure, including the placement of a stent. d) Congestive heart failure (CHF) (New York Heart Association [NYHA] class III or IV) within 6 months prior to enrollment or left ventricular ejection fraction (LVEF) less than lower limit of normal, per local institutional standards, within 6 months prior to enrollment. e) History of clinically significant (as determined by the treating physician) atrial arrhythmia or any history of ventricular arrhythmia. f) Venous thromboembolism, including deep venous thrombosis or pulmonary embolism, within 6 months prior to enrollment.
- Have uncontrolled hypertension (diastolic blood pressure > 90 mmHg; systolic 150 mmHg). Patients with hypertension should be under treatment on study entry to effect blood pressure control.
- Have poorly controlled diabetes, defined as HbA1c values over the previous year of > 7.5% (59 mmol/mol) on more than 3 occasions. Patients with preexisting, well-controlled diabetes are not excluded.
- The concomitant use of CYP3A inhibitors or inducers
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Recruiting | 03 Aug 2026 | 30 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Scemblix 40 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 400 | 12 | PRD10138998 |
Scemblix 20 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 400 | 12 | PRD9889410 |
Iclusig 45 mg film-coated tablets | Test | FILM-COATED TABLETS | ORAL USE | 30 | 12 | PRD12199385 |