Clinical Trials Register

Summary
EudraCT Number:	2018-001044-54
Sponsor's Protocol Code Number:	Bosupeg
National Competent Authority:	Finland - Fimea
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-03-15
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Finland - Fimea

A.2

EudraCT number

2018-001044-54

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A study of effect and safety of a new combination of drugs for chronic myeloid leukemia in chronic phase. Bosutinib is the basis treatment and patients will be randomized to receive or not to receive a long-acting low dose of Ropeginterferon.

Satunnaistettu, etenevä KML:n ensilinjan lääkehoitotutkimus: Lääkeaineen tehoa ja turvallisuutta mittaava tutkimus, jossa pieniannoksinen ropeginterferoni lisätään bosutinibihoitoon hiljattain diagnosoitua, kroonisessa vaiheessa olevaa kroonista myelooista meukemiaa sairastavilla potilailla.

A.3.2

Name or abbreviated title of the trial where available

BosuPeg

A.4.1

Sponsor's protocol code number

Bosupeg

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	St Olavs Hospital -Trondheim University Hospital
B.1.3.4	Country	Norway
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Pfizer Norge AS
B.4.2	Country	Norway
B.4.1	Name of organisation providing support	AOP Orphan Pharmaceuticals AG
B.4.2	Country	Austria
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	St Olavs Hospital
B.5.2	Functional name of contact point	Henrik Hjorth-Hansen
B.5.3	Address:
B.5.3.1	Street Address	PB 3250 Sluppen
B.5.3.2	Town/ city	Trondheim
B.5.3.3	Post code	7006
B.5.3.4	Country	Norway
B.5.4	Telephone number	4772825176
B.5.6	E-mail	henrik.hjorth-hansen@ntnu.no

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Bosulif
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Inc., 445 Eastern Point Road, MS 8260-1118, 06340 Groton, CT, USA
D.2.1.2	Country which granted the Marketing Authorisation	United States
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/11/932
D.3 Description of the IMP
D.3.1	Product name	Pegylated proline-interferon alpha 2b
D.3.2	Product code	AOP2014
D.3.4	Pharmaceutical form	Solution for injection in pre-filled pen
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Chronic myeloid leukemia at diagnosis-chronich phase

Diagnoosivaiheen krooninen myelooinen leukemia, kroonisessa vaiheessa

E.1.1.1

Medical condition in easily understood language

Chronic myeloid leukemia, a type of blood cancer

Krooninen myelooinen leukemia, verisyöpätyyppi

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

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.

Arvioida RoPegInterferonin liitämisen bosutinibihoitoon tuomaa tehoa syvän molekuläärisen vasteen ja hoitovapaan remissoin saavuttaneiden potilaiden määrän mahdollisella kasvulla.

E.2.2

Secondary objectives of the trial

• 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 evaluate the tolerability, of a step-by-step dose schedule for BOS initiation (BOSUSTEP substudy)
• To estimate the progression free, event-free and overall survival in each arm.
• To estimate the proportion of patients achieving a durable deep molecular response and secondary eligibility for treatment discontinuation.
• To compare the measurement of deep molecular response (by standard RTQPCR and digital droplet PCR (ddPCR),
• To estimate and compare the rate of successful treatment discontinuation after M48 in each arm

katso englanninkielinen teksti

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

A substudy of immunological parameters and a proteomic approach for identification of tumour markers is planned

katso englanninkielinen teksti

E.3

Principal inclusion criteria

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.
4) WOCBP must have a negative serum or urine pregnancy test at screening.
5) A male subject of fathering potential must use an adequate method of contraception to avoid conception throughout the study to minimize the risk of pregnancy.
6) Free subject, without guardianship nor subordination
7) Health insurance coverage.

katso englanninkielinen teksti

E.4

Principal exclusion criteria

1) Patients with BCR-ABL transcript other than M-BCR-ABL
2) Patients previously treated with tyrosine kinase inhibitors (TKIs).
3) 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, 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)
i) Other malignant disease during the last 5 years prior to the inclusion except non-melanoma 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.
4) Prohibited treatments and/or therapies: strong inhibitors/inducers of the CYP 3A4,
5) History / any condition for poor compliance to medical treatment.
6) Women who are pregnant or breastfeeding are not eligible for this study
7) Inability to freely provide consent through judiciary or administrative condition.
8) Ongoing participation to another clinical investigational study.

katso englanninkielinen teksti

E.5 End points

E.5.1

Primary end point(s)

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

Verrata molekulaarisen vasteen 4 (MR4) saavuttaneita 12 kuukauden kuluttua jokaisessa hoitohaarassa.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months of treatment

12 kuukauden hoidon jälkeen

E.5.2

Secondary end point(s)

• 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.
• The cumulative incidence of MR3, MR4, MR4.5 within the same periods in each arm.
• The rates of complete cytogenetic response (CCyR) at 3, 6, 12 months.
• The rates of undetectable molecular responses for the patients who achieved an MR4 and an MR4.5 in each arm.
• The rates of MR4 and MR4.5 by standard RTQPCR IS and digital droplet PCR (ddPCR) on the centralized molecular samples, for the patients who achieve an MR4 or better: comparison for sensitivity and accuracy of the 2 methods at key time points to be decided (ie Month 12 and Month 48)
• Time to and duration of CCyR, MR3, MR4, MR4.5.
• The proportion of patients eligible for randomization after 3 months of BOS
• 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.
• 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.
• Other endpoints for the BOSUSTEP substudy within the first three months of BOS:
- Any grade of diarrhea and GI toxicity
- Other AE > grade 1 related to BOS
- The final dose level of BOS by 3 months
- The proportion of patients with transient treatment discontinuation
- The proportion of patients with permanent treatment discontinuation
- Cytogenetic and Molecular responses assessed by BCR-ABL IS at M3 and M6
- The relationship between plasma residual concentration (Cmin) after dose escalation steps and tolerance / efficacy of BOS in a subset of patients (French cohort), and at M3 for Nordic patients who take part in ancillary projects.
• The progression free survival, the event-free survival and the overall survival. Occurrence and type of BCR-ABL TK mutation
• Quality of life assessment by QLQC30 and CML24 questionnaires at key time point (Day 1, M3, M6, M12, M24, M48, M54, M72)
• The proportion of patients achieving a durable deep molecular response and being eligible for treatment discontinuation at month 48. Sustained deep molecular response 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 M48)
• The proportion of patients in treatment free remission after 6, 12, 24 and 36 months of BOS discontinuation, from M48.

katso englanninkielinen teksti

E.5.2.1

Timepoint(s) of evaluation of this end point

See text above in E5.2.Many time points

Katso E5.2, useita aikapisteitä

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Bosutinib alone

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LPLV q1 2028

Viimeisen potilaan viimeinen käynti q1 2028

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

145

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

212

F.4.2.2

In the whole clinical trial

212

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Treatment according to guidelines in the patient's countries by advice of their treating physicians.

Hoito kansallisen hoitokäytännön ja hoitavan lääkärin suositusten mukaan.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Nordic CML Study group
G.4.3.4	Network Country	Norway
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	France Intregroupe LMC
G.4.3.4	Network Country	France

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-05-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-06-12

P. End of Trial
P.	End of Trial Status	Ongoing

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