Evaluation of Tolerability and Efficacy of Asciminib Hydrochloride Versus Nilotinib in Newly Diagnosed Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase
- Trial ID
- 2024-510947-71-00
- Protocol
- CABL001J12302
- Sponsor
- Novartis Pharma AG
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to assess the **tolerability** of asciminib compared to nilotinib in participants with newly diagnosed Chronic Myeloid Leukemia in Chronic Phase. This is evaluated with respect to the time to discontinuation of study treatment due to adverse events (TTDAE). Understanding the tolerability of these treatments is clinically relevant as it directly impacts patient adherence and long-term treatment outcomes in managing Chronic Myeloid Leukemia.
Secondary objectives include:
- Comparing the efficacy of asciminib versus nilotinib at all scheduled data collection time points.
- Evaluating the time to treatment discontinuation (TTD) for selected reasons of discontinuation.
- Assessing the effect of asciminib versus nilotinib on patient-reported disease-related symptoms, functioning, and health-related quality of life (HRQoL).
- Characterizing the safety and tolerability profile of asciminib versus nilotinib during the course of the study.
Participants
The clinical trial involves a total of **187 participants** diagnosed with **Chronic Myeloid Leukemia** in the chronic phase. The study population includes both male and female subjects aged 18 years and older. Participants were selected based on specific inclusion criteria, such as having a diagnosis of Chronic Myeloid Leukemia within three months, confirmed by cytogenetic analysis of the Philadelphia chromosome, and an Eastern Cooperative Oncology Group performance status of 0 or 1. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The participants are required to have adequate end organ function and meet certain laboratory value thresholds. The trial population includes a vulnerable group, indicating that special considerations are in place to ensure their safety and well-being during the study.
Plans and Procedures
The clinical trial is designed to evaluate the **tolerability** and efficacy of oral **asciminib hydrochloride** versus **nilotinib** in patients with newly diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase. This is a phase IIIb, multi-center, open-label, randomized study. The trial will involve a comparison between the two drugs, with **asciminib hydrochloride** serving as the test product and **nilotinib** as the comparator. The trial is expected to run from January 2023 to July 2031, with recruitment having started in November 2022.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, diagnosis, and organ function. Following randomization, participants will attend regular follow-up visits to monitor treatment effects, adverse events, and disease progression. The primary endpoint is the time to discontinuation of study treatment due to adverse events. Secondary endpoints include measures of efficacy, such as major molecular response (MMR) and progression-free survival, as well as safety assessments.
The expected length of participant involvement is up to 60 months, depending on the treatment arm. Conditions that may lead to early termination from the study include significant adverse events or disease progression. Participants will conclude their involvement with an end-of-study visit, where final assessments will be conducted to evaluate the overall impact of the treatment. The study is conducted under strict ethical guidelines, ensuring that all participants provide informed consent prior to participation.
Treatment
The clinical trial involves the administration of **nilotinib**, an experimental medication, in the form of a hard capsule. The active substance, nilotinib, is of chemical origin. The maximum daily dose is 600 mg, with a total maximum dose of 985,800 mg over a treatment period of 54 months. The medication is administered orally. When sourced locally from the commercial market, nilotinib may be over-labelled. In Romania, it may be packaged in HDPE bottles for clinical trials, differing from the commercial presentation in blisters. The shelf life is 60 months for HDPE bottles and 36 months for blister packs.
Another experimental medication used in the trial is **asciminib hydrochloride**, provided as a film-coated tablet. The active substance, asciminib hydrochloride, is also of chemical origin. The maximum daily dose is 80 mg, with a total maximum dose of 146,000 mg over a treatment period of 60 months. This medication is administered orally. For clinical trials, asciminib hydrochloride is packaged in bottles, contrasting with the commercial presentation in blisters. The shelf life is 48 months for HDPE bottles and 36 months for blister packs. Asciminib hydrochloride is designated as an orphan drug under the designation number EU/3/20/2261.
In this study, nilotinib serves as the comparator treatment, while asciminib hydrochloride is the test treatment. Both medications are administered orally, and participant compliance is monitored throughout the trial. The trial aims to assess the tolerability and efficacy of these treatments in patients with newly diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase.
Efficacy
The efficacy of the clinical trial will be assessed using several key endpoints. The primary endpoint is the **Time to Discontinuation of Study Treatment Due to Adverse Event (TTDAE)**, which is defined as the time from the first dose of study treatment to the discontinuation date due to an adverse event. Secondary efficacy endpoints include the achievement of Major Molecular Response (MMR) at and by all scheduled time points, MR4.0 and MR4.5 at and by all scheduled time points, Complete Hematological Response at and by all scheduled time points, and BCR::ABL1 ≤1% at and by all scheduled time points. Additional secondary endpoints involve the duration of MMR, MR4.0, MR4.5, time to first MMR, first MR4.0, first MR4.5, time to treatment failure, Event-Free Survival, Progression-Free Survival, Overall Survival, and Time to Treatment Discontinuation due to selected reasons.
Patient-reported outcomes (PRO) will also be evaluated as a secondary endpoint, focusing on changes from baseline in overall scores and individual scales of the EORTC QLQ-C30 and EORTC QLQ-CML24. The schedule for measuring these efficacy parameters will be aligned with the trial's protocol, ensuring that data collection occurs at all designated time points throughout the study duration. The analysis will utilize validated scales and laboratory tests to ensure the accuracy and reliability of the results. The trial is designed to provide comprehensive insights into the efficacy of oral asciminib versus nilotinib in patients with newly diagnosed Philadelphia Chromosome Positive Chronic Myelogenous Leukemia in Chronic Phase.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed informed consent must be obtained prior to participation in the study.
- Male or female patients ≥ 18 years of age
- Patients with CML-CP within 3 months of diagnosis
- Diagnosis of CML-CP (European Leukemia Network [ELN] 2020 criteria) with cytogenetic confirmation of the Philadelphia (Ph) chromosome. A cryptic Ph chromosome should be confirmed by metaphase Fluorescence in situ Hybridization (FISH) •Documented chronic phase CML will meet all the below criteria (Baccarani et al 2013): •< 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 (PLT) count ≥ 100 x 109/L (≥ 100,000/mm3) •No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly.
- Evidence of typical BCR::ABL1 transcript [e14a2 and/or e13a2] which is amenable to standardized RQ-PCR quantification by the central laboratory assessment. However, if a local qualitative assay, validated according to local regulation, from an accredited local laboratory has confirmed evidence of typical BCR::ABL1 transcript [e14a2 and/or e13a2], these results can be used for eligibility if the central Real Time Quantitative Polymerase Chain Reaction (RQ-PCR) results arrived are not available at the time of randomization.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Adequate end organ function as defined by: •Total bilirubin (TBL) < 3 x Upper Limit of Normal (ULN); patients with Gilbert’s syndrome may only be included if TBL ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN, •Creatinine Clearance (CrCl) ≥ 30 milliliters per minute (mL/min) as calculated using Cockcroft-Gault formula, Serum lipase ≤ 1.5 x ULN. For serum lipase > ULN - ≤ 1.5 x ULN, value must be considered not clinically significant and not associated with risk factors for acute pancreatitis.
- Patients must have the following laboratory values within normal limits or corrected to within normal limits with supplements prior to randomization: •Potassium (potassium increase of up to 6.0 mmol/L is acceptable if associated with CrCl* ≥ 90 mL/min)**, •Total calcium (corrected for serum albumin); (calcium increase of up to 12.5 mg/dl or 3.1 mmol/L is acceptable if associated with CrCl* ≥ 90 mL/min), •Magnesium (magnesium increase of up to 3.0 mg/dL or 1.23 mmol/L if associated with CrCl* ≥ 90 mL/min), •For patients with mild to moderate renal impairment (CrCl* ≥ 30 mL/min and <90 mL/min) - potassium, total calcium (corrected for serum albumin) and magnesium should be within normal limits or corrected to within normal limits with supplements prior to randomization. *CrCl as calculated using Cockcroft-Gault formula. ** pseudohyperkaliemia in case of thrombocytosis is not an exclusion criterion
Exclusion Criteria
- Previous treatment of CML with any other anticancer agents including chemotherapy and/or biologic agents or prior stem cell transplant, with the exception of hydroxyurea and/or anagrelide.
- Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required).
- Impaired cardiac function or cardiac repolarization abnormality including but not limited to any one of the following: • History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft (CABG) within 6 months prior to starting study treatment. • Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block). • QTcF ≥ 450 ms on the average of three serial baseline ECG (using the QTcF formula). If QTcF ≥ 450 ms and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTcF. • Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: • Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia, history of cardiac failure, or history of clinically significant/symptomatic bradycardia. • Concomitant medication(s) with a “Known risk of Torsades de Pointes” per crediblemeds.org that cannot be discontinued or replaced 7 days prior to starting study treatment by safe alternative medication. • Inability to determine the QTcF interval.
- 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; uncontrolled arterial or pulmonary hypertension, uncontrolled clinically significant hyperlipidemia).
- History of significant congenital or acquired bleeding disorder unrelated to cancer.
- Major surgery within 4 weeks prior to study entry or patients who have not recovered from prior surgery.
- 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.
- History of acute pancreatitis within 1 year prior to randomization or medical history of chronic pancreatitis.
- History of chronic liver disease leading to severe hepatic impairment, or ongoing acute liver disease.
- Known history of chronic Hepatitis B (HBV), or chronic Hepatitis C (HCV) infection. Testing for Hepatitis B surface antigen (HBs Ag) and Hepatitis B core antibody (HBc Ab/anti HBc) will be performed at screening. If anti-HBc is positive, HBV-DNA evaluation will be carried out at screening. A patient having positive HBV-DNA will not be enrolled in the study. Also, a patient with positive HBsAg will not be enrolled in the study. HCV Ab testing will also be performed at screening. For details on the criteria see Appendix 4.
- History of Human Immunodeficiency Virus (HIV) unless well-controlled on a stable dose of anti-retroviral therapy at the time of screening.
- Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study treatment (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery).
- Participation in a prior investigational study within 30 days prior to randomization or within 5 half-lives of the investigational product, whichever is longer.
- Pregnant or nursing (lactating) women
- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for a period of time after stopping study medication.
- Known hypersensitivity to the study treatment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 21 Nov 2022 | 30 |
 Czechia | Not Recruiting | 21 Nov 2022 | 31 |
 France | Not Recruiting | 21 Nov 2022 | 100 |
 Germany | Not Recruiting | 21 Nov 2022 | 145 |
 Greece | Not Recruiting | 21 Nov 2022 | 15 |
 Hungary | Not Recruiting | 21 Nov 2022 | 15 |
 Italy | Not Recruiting | 21 Nov 2022 | 25 |
 The Netherlands | Not Recruiting | 21 Nov 2022 | — |
 Romania | Not Recruiting | 21 Nov 2022 | 20 |
 Slovakia | Not Recruiting | 21 Nov 2022 | 6 |
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 |
|---|---|---|---|---|---|---|
ASCIMINIB HYDROCHLORIDE | Test | — | ORAL USE | 80 | 60 | SUB204228 |
NILOTINIB | Comparator | — | ORAL USE | 600 | 54 | SUB25225 |
NILOTINIB | Comparator | — | ORAL USE | 600 | 60 | SUB25225 |
NILOTINIB | Comparator | — | ORAL USE | 600 | 54 | SUB25225 |