A Open-Label Study Evaluating Tolerability and Efficacy of Navitoclax alone or in Combination with Ruxolitinib in Subjects with Myelofibrosis (REFINE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

AbbVie Deutschland GmbH & Co. KG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

23 Mar 2020 → 30 Jan 2025

Decision date (initial)

2024-04-26

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

AbbVie Inc.

External identifiers

EU CT number

2023-507276-53-00

EudraCT number

2017-001398-17

ClinicalTrials.gov

NCT03222609

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Pharmacogenetic, Efficacy, Others, Safety, Pharmacodynamic

Evaluate the effect of navitoclax alone or in combination with ruxolitinib on spleen volume

Secondary objectives 4

1. To assess the effect of navitoclax alone or in combination with ruxolitinib on total symptom score (TSS) as assessed by the Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0 diary
2. To evaluate the effect of navitoclax alone or in combination with ruxolitinib on bone marrow fibrosis
3. To determine the rate of anemia response associated with navitoclax alone or in combination with ruxolitinib
4. To describe the safety profile and PK profile observed with navitoclax alone or in combination with ruxolitinib

Conditions and MedDRA coding

Myelofibrosis

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-000478-PIP02-18

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Subjects ≥ 18 years of age
2. Subjects with documented diagnosis of Intermediate or High-risk Primary myelofibrosis, post-polycythemia vera myelofibrosis or postessential thrombocythemia myelofibrosis
3. Subjects classified as intermediate-2 or high-risk myelofibrosis, as defined by the Dynamic International Prognostic Scoring System (DIPSS)
4. Subject must be ineligible due to age, comorbidities, or unfit for unrelated or unmatched donor transplantation or unwilling to undergo stem cell transplantation at time of study entry
5. ECOG 0, 1, or 2
6. Cohort 1a only: Subject must have received ruxolitinib therapy for at least 12 weeks and be currently on a stable dose of ≥ 10 mg twice daily of ruxolitinib for ≥ 8 weeks prior to the 1st dose of navitoclax.
7. Cohort 1b only: Subject must have received treatment with ruxolitinib for ≥ 24 weeks with lack of efficacy OR for < 24 weeks with documented disease progression while on ruxolitinib OR for ≥ 28 days with intolerance defined as new RBC transfusion requirement
8. Cohort 2 only: Subject must have received prior treatment with JAK-2 inhibitor therapy for at least 12 weeks OR for ≥ 28 days complicated by development of red blood cell transfusion requirement (at least 2 units/month for 2 months) OR grade ≥ 3 adverse events of thrombocytopenia, anemia, hematoma and/or hemorrhage
9. Cohort 3 only: Subject must not have received prior treatment with a JAK-2 or BET inhibitor
10. Cohorts 1b and 3 only: Subject has at least 2 symptoms each with a score ≥ 3 or a total score of ≥ 12, as measured by the MFSAF v4.0 on at least 4 out of 7 days during screening prior to study drug dosing
11. Subject has splenomegaly defined as spleen palpation measurement ≥ 5 cm below costal margin or spleen volume ≥ 450 cm3 as assessed by MRI/CT
12. Subject must meet the laboratory parameters (adequate bone marrow, renal and hepatic function) as defined in the protocol.

Exclusion criteria 3

1. Splenic irradiation within 6 months prior to screening, or prior splenectomy.
2. Leukemic transformation (> 10% blasts in peripheral blood or bone marrow aspirate/biopsy).
3. Prior therapy with a BH3 mimetic compound or stem cell transplantation.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. ≥ 35% spleen volume reduction from baseline (SVR35) at Week 24 measured by MRI/CT.

Secondary endpoints 1

1. The secondary endpoints are at least 50% reduction in total symptom score from baseline measured by MFSAF 4.0; anemia response; and change in grade of bone marrow fibrosis.

Investigational products

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

Test 2

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

AbbVie Deutschland GmbH & Co. KG

Sponsor organisation

AbbVie Deutschland GmbH & Co. KG

Address

Knollstrasse

City

Ludwigshafen Am Rhein

Postcode

67061

Country

Germany

Scientific contact point

Organisation

AbbVie Deutschland GmbH & Co. KG

Contact name

Global Clinical Trials Helpdesk

Public contact point

Organisation

AbbVie Deutschland GmbH & Co. KG

Contact name

Global Clinical Trials Helpdesk

Third parties 5

Locations

4 EU/EEA countries · 16 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 6 files

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

Application history

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