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 (BosuPeg)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

St. Olavs Hospital HF

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 Nov 2018 → ongoing

Decision date (initial)

2024-11-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-517417-32-00

EudraCT number

2018-001044-54

ClinicalTrials.gov

NCT03831776

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

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

Secondary objectives 1

1. To compare cytogenetic and molecular response including kinetics through the treatment course. • To assess the proportion of patients eligible for randomization after the initial 3 months of BOS. • To determine and to compare safety and tolerability of the treatment in each arm. • To estimate reasons and cumulative rates of RoPegIFN and BOS discontinuation and the median dose of each drug by study arm. • To characterize the phenotype and function of leukemia stem cells and immune system at the diagnosis and during treatment and evaluate their impact on treatment responses (BosuPeg substudy) • To estimate the progression free, event-free and overall survival in each arm. • To assess the quality of life at different time points in each arm. • To estimate the proportion of patients achieving a durable deep molecular response and secondary eligibility for treatment discontinuation. • To estimate and compare the rate of successful treatment discontinuation in each ar

Conditions and MedDRA coding

CHRONIC MYELOID LEUKEMIA

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. 1) 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.
2. 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 1

1. 1) 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. To compare the rate of molecular response 4 (MR4 ) at 12 months in each treatment arm.

Secondary endpoints 14

1. The rates of molecular responses MR2 , MR3 , MR4 , MR4.5, at 1, 2, 3, 6, 9, 12, 15, 18, 21, 24 months and every 6 months thereafter in each arm.
2. The cumulative incidence of MR3 , MR4 , MR4.5 within the same periods in each arm
3. The rates of complete cytogenetic response (CCyR) at 3, 6, 12 months.
4. The rates of undetectable molecular responses for the patients who achieved an MR4 and an MR4.5 in each arm.
5. Time to and duration of CCyR, MR2 , MR3 , MR4 ,MR4.5 .
6. The proportion of patients eligible for randomization after 3 months of BOS
7. The rates and characteristics of severe adverse events (SAE) and adverse events (AE) related to BOS and RoPegIFN, from clinical and biological assessments: type and grade according to the NCI CTCAE v4.03.
8. The dose intensity of RoPegIFN and BOS administered during the first two years of study treatment. The cumulative incidence of discontinuation of the therapies. Reasons of discontinuation.
9. Other endpoints for the BosuPeg substudy: -Biomarkers of response, failure and toxicity. A) Fraction and phenotype of leukemic cells in the stem cell and progenitor cell compartment at debut and 3 and 12 months of treatment. B)Phenotype and function of immune cells at debut and 3 and 12 months of treatment. C)Non-CR-ABL mutations at debut and during treatment D)TCR clonality at debut and during treatment E)Changes in plasma cytokine profile during treatment
10. Other endpoints for the BosuPeg substudy: - Identification of novel potential targets for therapy of CML
11. The progression free survival, the event-free survival and the overall survival. Occurrence and type of BCR-ABL TK mutation
12. Quality of life assessment by QLQC30 and CML24 questionnaires at key time point (Day 1, M3, M6, M12, M24, at planned BOS-discontinuation, 6 and 24 months post discontinuation as well as at restart after discontinuation and 6 months after restart).
13. The proportion of patients achieving a durable deep molecular response and being eligible for treatment discontinuation at month 48–60 after minimally 2 years in continuous MR4 or better
14. The proportion of patients in treatment free remission after 6, 12, 24 and 36 months of BOS discontinuation.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

St. Olavs Hospital HF

Sponsor organisation

St. Olavs Hospital HF

Address

Prinsesse Kristinas G. 3

City

Trondheim

Postcode

7030

Country

Norway

Scientific contact point

Organisation

St. Olavs Hospital HF

Contact name

Henrik Hjorth-Hansen

Public contact point

Organisation

St. Olavs Hospital HF

Contact name

Henrik Hjorth-Hansen

Locations

4 EU/EEA countries · 17 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 23 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications