Open-label Study of Asciminib for CML-CP or CML-AP Patients With T315I Mutation Who Are Resistant, Intolerant or Ineligible to Ponatinib.

Official title

A Phase II, Multi-center, Prospective, Open-label Study of Asciminib in Patients With Chronic Myeloid Leukemia in Chronic Phase (CML-CP) or Accelerated Phase (CML-AP) With T315I Mutation Who Are Resistant, Intolerant or Ineligible to Ponatinib.

Overview

The objective of this Phase II study is to assess the potential of asciminib in managing CML-CP or CML-AP in patient carrying the T315I mutation. The presence of this mutation introduces treatment difficulties due to the limited available options. The study seeks to collect additional data on the effectiveness and safety of asciminib for these patients. By determining the drug's capacity to manage the disease and enhance patients outcomes, the study is designed to fill the unmet medical need and potentially offer a new therapeutic path for patients at a treatment deadlock.

Detailed description

This study is a Phase II, multi-center, single-arm prospective, open-label study that aims to evaluate the efficacy and safety of oral asciminib in patients with CML-CP or CML-AP with T315I mutation and after at least one tyrosine kinase inhibitors (TKI) and are resistant, intolerant, or ineligible for treatment with ponatinib.

Patients who have not been previously treated with asciminib would be enrolled in this study. The researchers will assess the effectiveness of asciminib in these participants, as well as evaluate its safety profile. The study will consist of two phases:

* The "core phase" which aims to answer the scientific and medical objectives. * An "extension phase" intended to provide opportunity to the participants to continue their ongoing treatment (asciminib) up to commercialization in France or decision to not commercialize asciminib for the study population (stopping development, refusal to extend marketing authorization, refusal of reimbursement).

Interventions

• Drug ABL001/Asciminib
  The study treatment for this clinical trial is an investigational drug called asciminib, which is marketed under the brand name Scemblix®. Asciminib is a compound that is being evaluated for its efficacy and safety in the treatment of the target condition. The minimum dose of asciminib to be administered in this study is 200 mg, while the maximum dose is 400 mg. The dose is planned as 200 mg twice a day (BID). The drug will be administered orally, allowing for convenient and non-invasive admin

Primary outcome measures

• Rate of BCR::ABL1 (Breakpoint Cluster Region Gene::Abelson proto-oncogene) IS (International Scale) ≤ 1% [MR2 (Molecular Response 2)] [Time frame: Month 12]

Secondary outcome measures (12)

• Kinetics of response: BCR::ABL1 IS (MR2, MMR, MR4.0, MR4.5, undetectable MR4.5) [Time frame: At 3, 6, 9, 12, 18 and 24 months]
• Estimate response to treatment MR2 at 12 months in participants with BCR::ABL1 IS > 1% at treatment initiation or maintenance of MR2 at 12 months in participants with MR2 at treatment initiation [Time frame: At 12 months]
• Time to Major Molecular Response (MMR) (for participants not in MMR at treatment initiation) [Time frame: up to 24 months]
• Duration of MMR [Time frame: up to 24 months]
• Time to Molecular Response 2 (MR2) (for participants not in MR2 at treatment initiation) [Time frame: up to 24 months]
• Duration of MR2 [Time frame: up to 24 months]
• Overall survival (OS) [Time frame: up to 24 months]
• Progression Free Survival (PFS) [Time frame: up to 24 months]
• Event Free Survival (EFS) [Time frame: up to 24 months]
• Failure Free Survival (FFS) [Time frame: up to 24 months]
• Adverse events (AEs) and Serious Adverse events (SAEs) [Time frame: up to 24 months]
• Deaths and reasons for death [Time frame: up to 24 months]

Eligibility criteria

Inclusion criteria

• Signed informed consent must be obtained prior to participation in the study.
• Male or female participants with a diagnosis of CML-CP or CML-AP ≥ 18 years of age.
• Patients with CML-CP or CML-AP with history of documented T315I mutation after at least one TKI and are resistant, intolerant, or ineligible to ponatinib (according to Investigator judgment)
• Not already treated with asciminib or another any allosteric TKI
• Failure (adapted from the 2020 \& 2013 ELN Guidelines) or intolerance to Ponatinib at the time of Screening.
• Ineligible to ponatinib according to Investigator (based on EU ponatinib SmPC)
• Evidence of typical BCR::ABL1 transcript or atypical transcripts at the time of Screening which are amenable to standardized or non-standardized RQ-PCR quantification.

Exclusion criteria

• Previous hematopoietic allogeneic stem-cell transplantation
• Cardiac or cardiac repolarization abnormality
• 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)
• 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)
• History of acute or chronic liver disease (i.e., cirrhosis; liver impairment)
• Known presence of significant congenital or acquired bleeding disorder unrelated to cancer
• 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
• 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
• Impairment of gastrointestinal (GI) function or GI 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)
• 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
• Pregnant or nursing (lactating) women
• Women of child-bearing potential
• Compound mutant T315I resistant to asciminib monotherapy (polyclonal ABL1 mutations including T315I can be enrolled) Other protocol-defined inclusion/exclusion criteria may apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

France · 6 centers

• Novartis Investigative Site — Bordeaux
• Novartis Investigative Site — Lille
• Novartis Investigative Site — Lyon
• Novartis Investigative Site — Nantes
• Novartis Investigative Site — Paris
• Novartis Investigative Site — Vandœuvre-lès-Nancy

Identifiers

NCT: NCT06514534 · CABL001AFR05 · 2024-516049-38-00

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗