Efficacy and Safety of Ropeginterferon Alfa-2b with Bosutinib in Chronic Myeloid Leukemia: A Randomized Prospective Trial
- Trial ID
- 2024-517417-32-00
- Protocol
- BosuPeg
- Sponsor
- St. Olavs Hospital HF
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to estimate the **efficacy** of adding RoPegIFN to Bosutinib (BOS) in patients with **Chronic Myeloid Leukemia** (CML) in terms of achieving a deep molecular response. This is clinically relevant as it aims to increase the proportion of patients who may achieve treatment-free remission, a significant milestone in the management of CML.
Secondary objectives include:
- Comparing cytogenetic and molecular response, including kinetics, throughout the treatment course.
- Assessing the proportion of patients eligible for randomization after the initial 3 months of BOS treatment.
- Determining and comparing the safety and tolerability of the treatment in each arm.
- Estimating reasons and cumulative rates of RoPegIFN and BOS discontinuation, and the median dose of each drug by study arm.
- Characterizing the phenotype and function of leukemia stem cells and the immune system at diagnosis and during treatment, and evaluating their impact on treatment responses.
- Estimating progression-free, event-free, and overall survival in each arm.
- Assessing the quality of life at different time points in each arm.
- Estimating the proportion of patients achieving a durable deep molecular response and secondary eligibility for treatment discontinuation.
- Estimating and comparing the rate of successful treatment discontinuation in each arm.
Participants
The clinical trial involves participants diagnosed with **chronic myeloid leukemia** in the chronic phase, specifically those who are BCR-ABL positive with major BCR-ABL transcripts (p210 b2a2(e13a2) and/or b3a2 (e14a2)). The study population includes both male and female subjects aged between 18 to 75 years. Participants are required to have an ECOG Performance Status of ≤ 2 and adequate organ function, as indicated by specific laboratory criteria. The trial does not include a vulnerable population. Participants must be newly diagnosed, within three months, and not previously treated for chronic myeloid leukemia except with hydroxyurea or anagrelide. Lifestyle considerations such as diet and physical activity are not specified. The sponsor has not provided information regarding the total number of participants in the trial.
Plans and Procedures
The clinical trial is designed to evaluate the **efficacy** and safety of long-acting low-dose **ropeginterferon alfa-2b** in patients with **chronic myeloid leukemia** (CML) who are treated with **bosutinib** from diagnosis. This is a randomized, prospective trial with a double-blind, controlled design. The trial is expected to run until December 31, 2030, with recruitment having started on April 29, 2019. Participants will be involved in the study for a maximum treatment period of 84 days for bosutinib and 21 days for ropeginterferon alfa-2b, with the possibility of early termination based on specific conditions such as adverse events or lack of efficacy.
The sequence of study visits includes an initial screening visit to confirm eligibility, followed by regular follow-up visits to monitor treatment response and safety. The inclusion visit will ensure that participants meet the criteria, such as being newly diagnosed with CML, having a complete hematologic response, and maintaining adequate organ function. Follow-up visits will occur at key intervals to assess primary and secondary endpoints, including molecular response rates and adverse events. The end-of-study visit will evaluate the overall outcomes and any long-term effects of the treatment.
Participants are expected to be involved in the study for the duration of their treatment period, with regular assessments to ensure compliance with the protocol. Conditions that may lead to early termination from the study include severe adverse events, failure to achieve the required response, or withdrawal of consent. The trial aims to provide valuable insights into the potential benefits of combining ropeginterferon alfa-2b with bosutinib in the treatment of CML, with the primary endpoint being the rate of molecular response 4 (MR4) at 12 months. Secondary endpoints include various molecular response rates, complete cytogenetic response rates, and quality of life assessments.
Treatment
The clinical trial involves the administration of **BOSUTINIB**, a tyrosine kinase inhibitor, as part of the treatment regimen for patients with chronic myeloid leukemia. **BOSUTINIB** is provided in an oral pharmaceutical form, with a maximum daily dose of 500 mg. The treatment period for **BOSUTINIB** is set at 84 days. The administration route is oral, and the medication is classified under the ATC code L01EA04. The chemical origin of the active substance ensures its role as a targeted therapy in the management of leukemia.
In addition to **BOSUTINIB**, the trial includes the use of **ROPEGINTERFERON ALFA-2B**, marketed as Besremi, which is administered as a solution for injection in a pre-filled pen. This medication is given via subcutaneous injection, with a maximum daily dose of 50 micrograms. The treatment duration for **ROPEGINTERFERON ALFA-2B** is 21 days. The active substance is a protein of other origin, specifically a pegylated proline-interferon alpha-2b, and is designated as an orphan drug. The pharmaceutical form is a solution for injection, and it is produced by AOP Orphan Pharmaceuticals GmbH. The inclusion of **ROPEGINTERFERON ALFA-2B** aims to enhance the efficacy of the treatment regimen by potentially increasing the proportion of patients achieving treatment-free remission.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the **molecular response** in patients with chronic myeloid leukemia treated with Bosutinib and Ropeginterferon Alfa-2b. The primary endpoint is the comparison of the rate of molecular response 4 (MR4) at 12 months in each treatment arm. Secondary endpoints include the rates of molecular responses MR2, MR3, MR4, and MR4.5 at various timepoints such as 1, 2, 3, 6, 9, 12, 15, 18, 21, and 24 months, and every 6 months thereafter. Additionally, the cumulative incidence of MR3, MR4, and MR4.5 within the same periods will be evaluated, along with the rates of complete cytogenetic response (CCyR) at 3, 6, and 12 months.
Other efficacy parameters include the time to and duration of CCyR, MR2, MR3, MR4, and MR4.5, as well as the proportion of patients eligible for randomization after 3 months of Bosutinib treatment. The study will also assess the rates and characteristics of severe adverse events and adverse events related to Bosutinib and Ropeginterferon Alfa-2b, using clinical and biological assessments according to the NCI CTCAE v4.03. Quality of life will be measured using QLQC30 and CML24 questionnaires at key timepoints, including Day 1, Month 3, Month 6, Month 12, Month 24, and at planned Bosutinib discontinuation, among others. The study aims to identify biomarkers of response, failure, and toxicity, and to explore novel potential targets for therapy of chronic myeloid leukemia.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed written informed consent form (ICF) before any procedure related to the study 2) Target Population a) Men and women, ages 18 to 75 years b) Newly diagnosed (≤ 3 months) BCR-ABL positive chronic myeloid leukemia in chronic phase c) Major BCR-ABL transcripts (p210 b2a2(e13a2) and/or b3a2 (e14a2)) d) Not previously treated for CML except with hydroxyurea or anagrelide e) ECOG Performance Status (ECOG PS) ≤ 2 f) Adequate organ function. i. Total bilirubin < 1,5 times the institutional Upper Limit of Normal (ULN) ii. Hepatic enzymes ASAT and ALAT < 2 times the institutional ULN iii. Serum Creatinine < 1.5 time the institutional ULN iv. Lipase < 1.5 time the institutional ULN 3) Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study. See section 9.2.2 “Pregnancy”. 4) WOCBP must have a negative serum or urine pregnancy test at screening. 5) Free subject, without guardianship nor subordination 6) Health insurance coverage.
- Eligibility criteria for randomization at 3 months: 1) Complete hematologic response achieved at M3 2) At least able to tolerate BOS 300mg daily 3) Platelet >75x109 /L and ANC>1 x109 /L 4) ASAT and ALAT< 3 ULN (< Grade 2) 5) Still fulfill other original inclusion and exclusion criteria, 6) HADS depression and anxiety scores <11 each: otherwise psychiatrist approval required for RoPegIFN Non-eligible pts may continue on BOS single drug, at investigator’s discretion.
Exclusion Criteria
- Patients with BCR-ABL transcript other than M-BCR-ABL 2) Patients previously treated with tyrosine kinase inhibitors (TKIs). 3) Inability to freely provide consent through judiciary or administrative condition. 4) Ongoing participation to another clinical investigational study. 5) Medical history and concurrent diseases: a) Hypersensitivity to any of the excipients of BOS or RoPegIFN b) Prior treatment with Interferon-α, contraindication to interferon-α, c) Autoimmune disorder, concomitant immunosuppressive treatment or corticosteroids, d) Pre-existing thyroid disease unless controlled with conventional treatment, autoimmune thyroiditis e) Chronic liver disease, f) Prior or ongoing severe psychiatric disease g) HIV positivity, chronic hepatitis B or C h) Uncontrolled or severe cardiac (NYHA Class III or IV) or pulmonary disease, Echocardiography with LVF < 45% or LLN, peak velocity of tricuspid regurgitant flow > 2,8 m/s Pulmonary arterial hypertension (PAH), QTc>450 ms (by Barrets correction) i) Other malignant disease during the last 5 years prior to the inclusion except nonmelanoma skin carcinoma or carcinoma in situ of the cervix, j) History of significant bleeding disorder unrelated to CML or diagnosed congenital bleeding disorder, k) Subjects with an uncontrolled undercurrent illness or any concurrent condition that, in the investigator’s opinion, would jeopardize the safety of the subject or compliance with the protocol. 6) Prohibited treatments and/or therapies: strong inhibitors/inducers of the CYP 3A4, 7) History / any condition for poor compliance to medical treatment. 8) Women who are pregnant or breastfeeding are not eligible for this study
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Denmark | Not Recruiting | 29 Apr 2019 | 34 |
 Finland | Not Recruiting | 29 Apr 2019 | 11 |
 Norway | Not Recruiting | 29 Apr 2019 | 64 |
 Sweden | Not Recruiting | 29 Apr 2019 | 55 |
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 |
|---|---|---|---|---|---|---|
Besremi 250 micrograms/0.5 mL solution for injection in pre-filled pen | Test | SOLUTION FOR INJECTION IN PRE-FILLED PEN | SUBCUTANEOUS INJECTION | 50 | 21 | PRD7034995 |
BOSUTINIB | Comparator | PHF00082MIG | ORAL | 500 | 84 | SCP154038 |