Long-acting Low Dose Ropeginterferon for Chronic Myeloid Leukemia Treated With Bosutinib From Diagnosis

Chronic Myeloid Leukemia Clinical Trial

— BosuPeg  

Official title:

A Study of Efficacy and Safety of Long-acting Low Dose Ropeginterferon in Patients With Chronic Myeloid Leukemia Treated With Bosutinib From Diagnosis: a Randomized Prospective Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03831776
• Other study ID #: BosuPeg TRIAL
• Secondary ID: 2018-001044-54
• Status: Recruiting
• Phase: Phase 2
• Start date: March 25, 2019
• Est. completion date: March 2028

Study information

• Verified date: April 2023
• Source: St. Olavs Hospital
• Contact: Henrik Hjorth-Hansen, md phd
• Phone: 0047 73598673
• Email: henrik.hjorth-hansen[@]ntnu.no
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To study the efficacy and safety of combination of Ro-Peg-interferon-α2b (RoPegIFN) with Bosutinib (BOS) in comparison to BOS monotherapy, as frontline therapy for newly diagnosed chronic myeloid leukemia patients, and to estimate efficacy of the addition of RoPegIFN to BOS in terms of deep molecular response with the aim of increasing the proportion of patients who may achieve treatment free remission. (NCMLSG study #NordCML012)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 212
• Est. completion date: March 2028
• Est. primary completion date: February 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Signed written informed consent form (ICF) before any procedure related to the study
• Newly diagnosed (= 3 months) BCR-ABL positive chronic myeloid leukemia (CML) in chronic phase
• Major BCR-ABL transcripts (p210 b2a2(e13a2) and/or b3a2 (e14a2)
• Not previously treated for CML except with hydroxyurea or anagrelide
• ECOG Performance Status (ECOG PS) = 2
• Adequate organ function: Total bilirubin < 1,5 times the institutional Upper Limit of Normal (ULN); Hepatic enzymes ASAT and ALAT < 2 times the institutional ULN; Serum Creatinine < 1.5 time the institutional ULN; Lipase < 1.5 time the institutional ULN
• Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study.
• WOCBP must have a negative serum or urine pregnancy test at screening.
• Free subject, without guardianship nor subordination
• Health insurance coverage

Exclusion Criteria:

• Patients with BCR-ABL transcript other than M-BCR-ABL
• Patients previously treated with tyrosine kinase inhibitors (TKIs).
• Inability to freely provide consent through judiciary or administrative condition.
• Ongoing participation to another clinical investigational study.
• Medical history and concurrent diseases: a) Hypersensitivity to any of the excipients of BOS or RoPegIFN, b) Prior treatment with Interferon-a, contraindication to interferon-a, c) Autoimmune disorder, concomitant immunosuppressive treatment or corticosteroids, d) Pre-existing thyroid disease unless controlled with conventional treatment, auto-immune 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)
• Other malignant disease during the last 5 years prior to the inclusion except non-melanoma skin carcinoma or carcinoma in situ of the cervix,
• History of significant bleeding disorder unrelated to CML or diagnosed congenital bleeding disorder,
• 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.
• Prohibited treatments and/or therapies: strong inhibitors/inducers of the CYP 3A4,
• History / any condition for poor compliance to medical treatment.
• Women who are pregnant or breastfeeding are not eligible for this study

Related Conditions & MeSH terms

• Chronic Myeloid Leukemia
• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid

Intervention

Drug:
• Bosutinib
Bosutinib, provided by Pfizer, starting dose of 200mg QD and stepwise dose escalation (> 300 mg/d > 400 mg/d) during the first three months. A pharmacological study will be performed in the French cohort (BOSUSTEP Substudy). BOS residual plasma concentration (Cmin) will be checked after initiation, before each dose step in the French cohort, and at M3 also for Nordic patients in ancillary studies.
• Ropeginterferon
Ro-Peg-Interferon a2b will be supplied by AOP Orphan to be administered by subcutaneous injections from prefilled injection pens. RoPegIFN will be given in an open-label fashion. Patients assigned to RoPegIFN will start with 50 µg injected subcutaneously every 14 days, in combination with Bosutinib.

Locations

Country	Name	City	State
Denmark	Aalborg university hospital	Aalborg
Denmark	Aarhus ...	Aarhus
Denmark	Copenhagen ...	Copenhagen
Denmark	Odense Universitetshospital	Odense
Finland	Comprehensive Cancer Center, Hematology	Helsinki
Norway	Haukeland Universitetssjukehus	Bergen
Norway	Oslo Universitetssykehus	Oslo
Norway	Stavanger Universitetssjukehus	Stavanger
Norway	Universitetssykehuset Nord Norge	Tromsø
Norway	St Olavs Hospital	Trondheim
Sweden	Göteborg ....	Göteborg
Sweden	Universitetssjukhuset Linköping	Linköping
Sweden	Skåne University Hospital	Lund
Sweden	Universitetssjukhuset Örebro	Örebro
Sweden	Karolinska Universitetssjukhus	Stockholm
Sweden	Sundsvall ...	Sundsvall
Sweden	Norrlands Universitetssjukhus	Umeå
Sweden	University Hospital	Uppsala

Sponsors (10)

Lead Sponsor	Collaborator
St. Olavs Hospital	Haukeland University Hospital, Helse Stavanger HF, Henri Mondor University Hospital, Hôpital Mignot, Versailles Paris, Hôpital René Huguenin, Odense University Hospital, Oslo University Hospital, University Hospital of North Norway, Uppsala University Hospital

Countries where clinical trial is conducted

Denmark,  Finland,  Norway,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of molecular response 4 (MR4)	Molecular response 4 (MR4) is defined by either a positive BCR-ABL/ABL ratio = 0.01% on the international scale (IS) or by undetectable BCR-ABL with the analysis of at least 10000 copies of ABL or 24000 copies of GUS (according to the ELN recommendations by N. Cross et al., Leukemia 2015)	12 months
Secondary	Rate of molecular response MR2, MR3, MR4, MR4.5 from 1 month up to 24 months and every 6 months thereafter		2 years
Secondary	Cumulative incidence of molecular response MR3, MR4, MR4.5		2 years
Secondary	Rate of complete cytogenetic response (CCyR) up to 12 months		12 months
Secondary	Rate of undetectable molecular response for patients who achieved molecular response MR4 and MR4.5		2 years
Secondary	Time to and duration of CCyR, MR3, MR4, MR4.5		2 years
Secondary	proportion of patients eligible for randomization after 3 months of Bosutinib		3 months
Secondary	rate and characteristics of severe adverse events (SAE)	type and grade according to the NCI CTCAE v4.03	2 years
Secondary	Dose intensity of RoPegIFN and Bosutinib		2 years
Secondary	Cumulative incidence of discontinuation of the therapies, incl. reasons for discontinuation		2 years
Secondary	Quality of life assessment by QLQC30 questionnaire up to 6 years at key time point (Day 1, month 3, month 6, month 12, month 24, month 48, month 54, month 72)		6 years
Secondary	Quality of life assessment by CML24 questionnaire up to 6 years at key time point (Day 1, month 3, month 6, month 12, month 24, month 48, month 54, month 72)		6 years
Secondary	The proportion of patients achieving a durable deep molecular response and being eligible for treatment discontinuation at month 48	Sustained deep molecular response (MR) criteria will be defined according updated data and ELN guidelines before the first patient will achieve month 48 (at least a MR4 over a 12 months period and confirmed on the last centralized measurement at month 48	4 years