Safety and efficacy of treatment combination with ponatinib and asciminib in chronic myeloid leukemia patients resistant to ponatinib and/or asciminib

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Grupo Espanol De Leucemia Mieloide Cronica (GELMC)

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2026-06-01

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Academic study: Conduct of the study with non‑monetary support

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To evaluate the proportion of patients with molecular response 2 (MR2) of asciminib and ponatinib combination at 6 months.

Secondary objectives 14

1. To describe PK values among patient treated with asciminib and ponatinib.
2. To evaluate the proportion of patients with complete cytogenetic response (CCyR) of asciminib and ponatinib combination at 6 months.
3. To describe the safety and tolerability profile of asciminib and ponatinib combination.
4. To evaluate the proportion of patients treated with asciminib and ponatinib combination who achieve cytogenetic response at 12 months.
5. To determinate molecular response (MR) rates.
6. To evaluate hematologic response rate of asciminib and ponatinib combination.
7. To determinate rate of discontinuation due to AEs during the treatment with asciminib and ponatinib combination.
8. To determinate dose reductions and dose interruptions due to AEs during the treatment with asciminib and ponatinib combination.
9. To evaluate duration of response (DoR) of patients treated with asciminib and ponatinib combination.
10. Time to response (TTR) of patients treated with asciminib and ponatinib combination.
11. To characterize rate of progression to accelerated phase (AP-) or blast phase (BP-) CML.
12. To determinate progression free survival (PFS) of patients treated with asciminib and ponatinib combination.
13. To determinate event free survival (EFS) of patients treated with asciminib and ponatinib combination.
14. To determinate overall survival (OS) of patients treated with asciminib and ponatinib combination.

Conditions and MedDRA coding

Chronic Myeloid Leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 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.
2. Patients ≥ 18 years old.
3. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
4. Have adequate renal function as defined by the following criterion: serum creatinine ≤ 1.5 × upper limit of normal (ULN).
5. 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.
6. Have normal pancreatic status as defined by the following criterion: Serum lipase and amylase ≤ 1.5 × ULN.
7. 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.
8. 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.
9. Provide written informed consent.

Exclusion criteria 22

1. 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.
2. Have a significant bleeding disorder unrelated to CML.
3. Have a history of alcohol abuse according to medical records.
4. Have a history of either acute pancreatitis within 1 year of study or chronic pancreatitis.
5. Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drug.
6. 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.
7. Known hypersensitivity or severe reaction to ponatinib or excipients of ponatinib.
8. Known hypersensitivity or severe reaction to ascinimib or excipients of ascinimib.
9. Females who are pregnant or lactating.
10. Receipt of live (including attenuated) vaccines or anticipation of need for such vaccines during the study.
11. Inability or unlikeliness to comply with the dose schedule and study evaluations, in the opinion of the investigator.
12. 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.
13. 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.
14. Inability of the participant (or guardian, or legally authorized representative) to comprehend the ICF or unwillingness to sign the ICF.
15. 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.
16. 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)
17. Are taking medications with a known risk of Torsades de Pointes.
18. 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.
19. 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.
20. 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.
21. 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.
22. The concomitant use of CYP3A inhibitors or inducers

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. MR2 is defined as ≤ 1% BCR::ABL1 at 6 months.

Secondary endpoints 14

1. Cmax and Tmax will be determinate.
2. A complete cytogenetic response (CCyR) is defined as absence of the Ph among at least 20 cells in meta phase in a bone marrow aspirate at 6 months.
3. Type, frequency, and severity of adverse events.
4. A complete cytogenetic response (CCyR) is defined as absence of the Ph among at least 20 cells in metaphase in a bone marrow aspirate at 12 months.
5. MR2, MR3/MMR, MR4, and MR4.5 at 3­month intervals and MR1 (≤ 10% BCR::ABL1) at 3 months.
6. Complete hematologic response (CHR) at 3 months.
7. Number of patients who discontinue permanently treatment with asciminib and/or ponatinib due to AEs.
8. Number of patients who interrupt the dose of treatment and dose reductions with asciminib and ponatinib due to AEs.
9. Duration of response is defined as the time between date of the first efficacy evaluation that the subject has met all criteria for BRC::ABL<1% and progression.
10. TTR is defined as the time between date of first dose of combination and the first efficacy evaluation that the subject has met all criteria for BRC::ABL<1%.
11. Number of patients who progress to accelerated phase (AP-) or blast phase (BP-) CML.
12. PFS is defined as the time from the date of first dose of combination to the date of first documented disease progression.
13. EFS is defined as the time from the date of first dose of combination to the date of first documentation of an event (disease progression or death) or permanent discontinuation of asciminib or ponatinib.
14. OS is defined as the time from the date of first dose of combination to the date of death (any cause).

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Grupo Espanol De Leucemia Mieloide Cronica (GELMC)

Sponsor organisation

Grupo Espanol De Leucemia Mieloide Cronica (GELMC)

Address

Carre De Balmes 243 Escalera A 5º 1ª

City

Barcelona

Postcode

08006

Country

Spain

Scientific contact point

Organisation

Grupo Espanol De Leucemia Mieloide Cronica (GELMC)

Contact name

Gemma Sánchez

Public contact point

Organisation

Grupo Espanol De Leucemia Mieloide Cronica (GELMC)

Contact name

Gemma Sánchez

Third parties 2

Locations

1 EU/EEA country · 10 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 15 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications