Clinical trial NCT06514534: 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.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Chronic Myeloid Leukemia (CML)
Keywords: Asciminib
ABL001
Abelson proto-oncogene (ABL1)
Chronic Myelogenous Leukemia (CML)
BCR::ABL1
Phase II
Tyrosine kinase inhibitor (TKI)
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2024-07-23
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Single-arm, open-label study
Primary purpose: TREATMENT

Brief summary: 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).

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.

Primary outcomes:
measure: Rate of BCR::ABL1 (Breakpoint Cluster Region Gene::Abelson proto-oncogene) IS (International Scale) ≤ 1% [MR2 (Molecular Response 2)]
timeFrame: Month 12
Secondary outcomes:
measure: Kinetics of response: BCR::ABL1 IS (MR2, MMR, MR4.0, MR4.5, undetectable MR4.5)
timeFrame: At 3, 6, 9, 12, 18 and 24 months
measure: 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
timeFrame: At 12 months
measure: Time to Major Molecular Response (MMR) (for participants not in MMR at treatment initiation)
timeFrame: up to 24 months
measure: Duration of MMR
timeFrame: up to 24 months
measure: Time to Molecular Response 2 (MR2) (for participants not in MR2 at treatment initiation)
timeFrame: up to 24 months
measure: Duration of MR2
timeFrame: up to 24 months
measure: Overall survival (OS)
timeFrame: up to 24 months
measure: Progression Free Survival (PFS)
timeFrame: up to 24 months
measure: Event Free Survival (EFS)
timeFrame: up to 24 months
measure: Failure Free Survival (FFS)
timeFrame: up to 24 months
measure: Adverse events (AEs) and Serious Adverse events (SAEs)
timeFrame: up to 24 months
measure: Deaths and reasons for death
timeFrame: up to 24 months
Other outcomes:
Locations:
city: Lyon
country: France
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: