Study to evaluate the efficacy and safety of fedratinib in combination with CC-486 in patients suffering from myelofibrosis in acute phase.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Martin-Luther-Universitaet Halle-Wittenberg

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

3 Nov 2022 → 16 Apr 2026

Decision date (initial)

2024-12-13

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-519227-22-00

EudraCT number

2021-003650-23

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

Phase I: To determine the safety and tolerability of the drug fedratinib in combination with CC-486
Phase II: To determine the rate of best response [clinical improvement (CI), partial remission (PR), or complete remission (CR)] of the combination therapy of fedratinib and CC-486

Secondary objectives 1

1. Determine the duration of best response (DOR), percentage of subjects with at least 50% reduction in MF-associated symptoms, durability of symptom response, percentage of subjects with a spleen response, time to spleen response, durability of spleen response, percentage of subjects that demonstrate an anemia response, progression free survival (PFS), overall survival (OS), proportion of subjects who transit to allogeneic SCT. - safety and tolerability of fedratinib in combination with CC-486. - effectiveness of the risk mitigation strategy for gastrointestinal events and Encephalopathy Health-Related Outcomes using specific questionnaires

Conditions and MedDRA coding

Myeloproliferative neoplasm in accelerated phase (MPN-AP)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. - Males and females at least 18 years of age at the time of signing the informed consent form - Diagnosis of MPN-AP (defined by a blast count of 10%-19% peripherally or in the bone marrow) at the time of diagnosis or at any time during the course of a known primary myelofibrosis (PMF), post– polycythemia vera (PV) myelofibrosis (MF) or post–essential thrombocythemia (ET) MF - Eastern Cooperative Oncology Group (ECOG) Performance Score (PS) of 0, 1 or 2 - Prior to Day 1 of study therapy, any treatment-related toxicities from prior therapy must have resolved to Grade 1 or pretreatment baseline of last therapy - Subject is willing and able to adhere to the study visit schedule and the protocol-specifiec procedures - Subject must understand and voluntarily sign an ICF prior to any studyrelated assessments/procedures being conducted

Exclusion criteria 1

1. - Subject with thiamine deficiency, defined as thiamine levels in whole blood below normal range according to institutional standard and not demonstrated to be corrected prior to start of trial treatment - Known or suspected hypersensitivity to azacitidine, mannitol, or its constituents - Subjects who are known not to tolerate a daily dose of 400 mg of XML File Identifier: jBFy3zzNZH8irDQXaSaKgq6jKT8= Page 15/30 fedratinib - The following laboratory values within 14 days prior to first dose: - Platelet count <50 x 109/L - Absolute neutrophil count (ANC) < 1.0 x 109/L - White blood count (WBC) > 100 x 109/L - Myeloblasts ≥ 20 % in peripheral blood - Serum creatinine > 2.5 x upper limit of normal (ULN) - Serum amylase or lipase > 1.5 x ULN - Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 x ULN - Total bilirubin > 1.5 x ULN, subject's total bilirubin between 1.5 – 3.0 x ULN are eligible if the direct bilirubin fraction is < 25 % of the total bilirubin. - Subject with prior history of Encephalopathy, including WE - Subject with signs or symptoms of Encephalopathy, including WE (eg, severe ataxia, ocular paralysis or cerebellar signs) - Subject with concomitant treatment with or use of pharmaceutical, herbal agents or food known to be strong inducers of cytochrome P450 3A4 (CYP3A4), or dual CYP2C19 and CYP3A4 inhibitors - Subject on any ongoing chemotherapy, hypomethylating agent (HMA), immunomodulatory drug therapy (eg, thalidomide, interferon-alpha), anagrelide, immunosuppressive therapy, systemic corticosteroids > 10 mg/day prednisone or equivalent. - Subject on treatment with aspirin with doses > 150 mg daily - Subject with diagnosis of active liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis) - Subject with prior malignancy other than the disease under study unless the subject has not required treatment for the malignancy for at least 3 years prior to enrollment. - Significant active cardiac disease within the previous 6 months, including: a. New York Heart Association (NYHA) class IV congestive heart failure; b. Unstable angina or angina requiring surgical or medical intervention; and/or c. Myocardial infarction - Subject with presence of any significant gastric or other disorder that would inhibit absorption of oral medication - Subject who is unable to swallow capsule - Subject is pregnant or lactating female

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Phase I: physical examinations, laboratory tests, AEs, serious AEs (SAEs), ECGs, and vital signs. - DLTs (dose limiting toxicity) will be used to establish the MTD of fedratinib in combination with CC-486. The SRC will determine the RP2D and schedule based on safety data of the combination of fedratinib and CC-486. Phase II: - Best response to the combination therapy at week 24 according to the IWG-MRT and the ELN consensus report. This includes CI, PR and CR

Secondary endpoints 1

1. duration of response - Change in MF-associated symptoms measured by MFSAF - Time from the first observation of best symptom response to first documented loss of symptom response - Spleen response by palpation - Time from the first treatment dose to disease progression, relapse or death - proportion of subjects who transit to allogeneic SCT - proportion of subjects that demonstrate an anemia - Analysis of incidence of subjects with a CTCAE Grade ≥3 of nausea, diarrhea, vomiting or occurrence o

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Martin-Luther-Universitaet Halle-Wittenberg

Sponsor organisation

Martin-Luther-Universitaet Halle-Wittenberg

Address

Ernst-Grube-Strasse 40, Kroellwitz Kroellwitz

City

Halle (Saale)

Postcode

06120

Country

Germany

Scientific contact point

Organisation

Martin-Luther-Universitaet Halle-Wittenberg

Contact name

Prof. Dr. med. Haifa Kathrin Al-Ali

Public contact point

Organisation

Martin-Luther-Universitaet Halle-Wittenberg

Contact name

Prof. Dr. med. Haifa Kathrin Al-Ali

Locations

1 EU/EEA country · 8 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 5 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