Open-label study of Asciminib for CML-CP or CML-AP patients with T315I mutation who are resistant, intolerant or ineligible to ponatinib

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma S.A.S.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

18 Feb 2025 → ongoing

Decision date (initial)

2024-11-05

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Novartis Pharma S.A.S.

External identifiers

EU CT number

2024-516049-38-00

ClinicalTrials.gov

NCT06514534

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

Estimate response to treatment MR2 (BCR::ABL1 IS ≤ 1%) at 12 months.

Secondary objectives 2

1. To evaluate additional parameters of the efficacy of asciminib.
2. To evaluate the safety and tolerability profile of asciminib.

Conditions and MedDRA coding

CML-CP or CML-AP patients with T315I mutation

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Signed informed consent must be obtained prior to participation in the study.
2. Male or female patients with a diagnosis of CML-CP or CML-AP ≥ 18 years of age.
3. Patients with CML-CP or CML-AP with history of documented T315I mutation after at least one TKI treatment, who are resistant, intolerant, or ineligible to ponatinib (according to Investigator judgment) Documented CML-CP will meet all the below European Leukemia Network (ELN) 2020 criteria (Hochhaus et al 2020): • < 15% blasts in peripheral blood and bone marrow, • < 30% blasts plus promyelocytes in peripheral blood and bone marrow, • < 20% basophils in the peripheral blood, • Platelet count ≥ 100 x 109/L (≥ 100,000/mm3), • No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly. Documented CML-AP will meet all the below ELN 2013 criteria (Baccarani et al 2013): • 15-29% blasts in peripheral blood or bone marrow • ≥ 30% blasts plus promyelocytes (with blasts <30%) in peripheral blood or bone marrow , • ≥ 20% basophils in peripheral blood • <100 x10(9)/L platelets unrelated to therapy, • Clonal chromosome abnormalities in Ph1 cells (CCA/Ph1), major route, on treatment
4. Not already treated with asciminib or another any allosteric inhibitor
5. Failure (adapted from the ELN guidelines 2020 and ELN Guidelines 2013) or intolerance to Ponatinib at the time of Screening.Treatment failure is defined for CML-CP and CML-AP patients as follows (Hochhaus et al 2020). Patients must meet at least 1 of the following criteria: o 3 months after the initiation of therapy: BCR::ABL1 IS ratio > 10% if confirmed within 1-3 months o 6 months after the initiation of therapy: BCR::ABL1 IS ratio > 10% o 12 months after initiation of therapy: BCR::ABL1 IS ratio > 1% o At any time after the initiation of therapy: BCR::ABL1 IS ratio > 1% o At any time after the initiation of therapy: development of new BCR::ABL1 mutations (only T315I in this study) which potentially cause resistance o At any time after the initiation of therapy: new high-risk additional cytogenetic abnormalities o Intolerance: o Non-hematologic intolerance: Patients with any Grade 3 or 4 toxicity while on therapy, or with persistent (i.e. ≥ 3 months) chronic Grade 2 toxicity, unresponsive to optimal management, including dose adjustments (unless dose reduction is not considered in the best interest of the patient if response is already suboptimal) o Hematologic intolerance: Patients with Grade 3 or 4 toxicity (absolute neutrophil count [ANC] or platelets) while on therapy that is recurrent after dose reduction to the lowest doses recommended by the Marketing Authorization Holder
6. Ineligible to ponatinib according to Investigator (based on Ponatinib SmPC)
7. Evidence of typical BCR::ABL1 transcript [e14a2 and/or e13a2] or atypical transcripts at the time of Screening which are amenable to standardized or non-standardized real-time quantitative PCR (RQ-PCR) quantification.

Exclusion criteria 15

1. Previous hematopoietic allogeneic stem-cell transplantation
2. Cardiac or cardiac repolarization abnormality, including any of the following: • History within 6 months prior to starting study treatment of myocardial infarction, angina pectoris, coronary artery bypass graft (CABG), clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade Atrioventricular (AV) block (e.g., bifascicular block, Mobitz Type II and III degree AV block) • QT interval corrected by Fridericia’s formula (QTcF) at Screening ≥ 470 msec (male patients), ≥450 msec (female patients) • Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: o Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia Concomitant medications with a “Known risk of TdP” per wwwcrediblemeds.org/ that cannot be discontinued or replaced 7 days prior to starting study drug by safe alternative medication. o Inability to determine the QTcF interval
3. 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)
4. History of clinical acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis (except if ponatinib-induced and completely resolved at time of Screening)
5. History of acute or chronic liver disease (i.e. cirrhosis; liver impairment)
6. Known presence of significant congenital or acquired bleeding disorder unrelated to cancer
7. History of other active malignancy within 3 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively
8. Known history of Human Immunodeficiency Virus (HIV), chronic Hepatitis B Virus (HBV), or chronic Hepatitis C Virus (HCV) infection. Testing for Hepatitis B surface antigen (HBs Ag) and Hepatitis B core antibody (HBcAb / anti HBc) will be performed at Screening
9. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery)
10. Treatment with medications that meet one of the following criteria and that cannot be discontinued at least one week prior to the start of treatment with study treatment: • Moderate or strong inducers of CYP3A • Moderate or strong inhibitors of CYP3A
11. Previous known/ suspected hypersensitivity to asciminib or any of its excipients.
12. Participation in a prior investigational study within 30 days prior to ICF’s signature or within 5 half-lives of the investigational product, whichever is longer
13. Pregnant or nursing (lactating) women
14. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 3 days after last dose of asciminib. Highly effective contraception methods include: • Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception • Female sterilization (have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks before taking study treatment). In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment • Male sterilization (at least 6 months prior to Screening). The vasectomized male partner should be the sole partner for that patient. • Use of oral, injected or implanted hormonal methods of contraception or placement of an intrauterine device or intrauterine system or other forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for example hormone vaginal ring or transdermal hormone contraception. • In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment. • Women are considered post-menopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks before taking study treatment. In the case of oophorectomy alone, women are considered post-menopausal and not of childbearing potential only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
15. Compound mutant T315I resistant to asciminib monotherapy (Eide et al 2019, Sponseiler et al 2024), (polyclonal ABL1 mutations including T315I can be enrolled)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Rate of BCR::ABL1 IS ≤ 1% (MR2) at 12 months.

Secondary endpoints 13

1. Kinetics of response: BCR::ABL1 IS (MR2, major molecular response (MMR), MR4.0, MR4.5, undetectable MR4.5) at and by 3, 6, 9, 12, 18 and 24 months for all patients,
2. Estimate response to treatment MR2 at 12 months in patients with BCR::ABL1 IS > 1% at treatment initiation or maintenance of MR2 at 12 months in patients with MR2 at treatment initiation,
3. Time to MMR (for patients not in MMR at treatment initiation),
4. Duration of MMR patient
5. Time to MR2 (for patients not in MR2 at treatment initiation),
6. Duration of MR2,
7. Overall survival (OS),
8. Progression Free Survival (PFS),
9. Event Free Survival (EFS),
10. Failure Free Survival (FFS).
11. Number of patients with an AE (frequency),
12. Description/severity (grade of severity) of AE (all AE, serious or not serious AE, related and not related AE), and number of patients who discontinued the treatment due to AE,
13. Deaths and reasons for death.

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma S.A.S.

Sponsor organisation

Novartis Pharma S.A.S.

Address

8-10 Rue Henri Sainte Claire Deville

City

Rueil Malmaison

Postcode

92500

Country

France

Scientific contact point

Organisation

Novartis Pharma S.A.S.

Contact name

Pierre-Louis Lecoq

Public contact point

Organisation

Novartis Pharma S.A.S.

Contact name

Pierre-Louis Lecoq

Third parties 3

Locations

1 EU/EEA country · 7 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

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

Documents 11 files

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

Application history

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