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Fedratinib in Combination with CC-486, a hypomethylating agent, in patients with accelerated Phase Myelofibrosis

Organizational Data

DRKS-ID:
DRKS00030348
Recruitment Status:
Recruiting ongoing
Date of registration in DRKS:
2022-10-13
Last update in DRKS:
2023-01-09
Registration type:
Prospective

Acronym/abbreviation of the study

FAMy

URL of the study

No Entry

Brief summary in lay language

There is currently no standard therapy for myelofibrosis in the accelerated (advanced) phase. Further progression of myelofibrosis can lead to the development of acute leukemia. Therefore, treatment with the drug fedratinib in combination with a second drug, CC-486, will be investigated in this study. The aim is to investigate the tolerability and efficacy of the combination treatment in this disease. The results of this study will help to identify whether fedratinib in combination with CC-486 can become a good treatment option for patients with myelofibrosis in advanced disease phase. The first phase of the study will evaluate safety and tolerability. Furthermore, the optimal dosage of both drugs will be found out in this phase. In the second phase of the study, the efficacy of the combination treatment will be investigated.

Brief summary in scientific language

This is a clinical trial in patients with myelofibrosis in accelerated phase (MPN-AP), for which no standard therapy exists to date. The study patients receive a combination therapy consisting of the drug fedratinib and the hypomethylating substance CC-486 (oral azacitidine). The combination therapy is planned to be administered over a period of 24 months and will be administered as a continuous tablet therapy in two phases. In the first phase, the safety, tolerability and recommended dosage of the drugs will be investigated. In the second phase of the study, patients will be treated with the dosage regimen determined in the first phase to evaluate the efficacy of the efficacy of the combination therapy.

Health condition or problem studied

Free text:
Myeloproliferative neoplasm in accelerated phase (MPN-AP)
Healthy volunteers:
No

Interventions, Observational Groups

Arm 1:
Inrebic® 100 mg hard capsules (fedratinib), 200mg, 300mg, 400mg/day (depending on dose level) p.o. (hard capsule) for 28 days in combination with mit CC-486 300mg/day p.o. (tablets) for 14 days per cycle until the onset of unacceptable toxicities, lack of therapeutic effects, or progression of disease

Endpoints

Primary outcome:
Phase I: determine the fedratinib maximum tolerated dose (MTD) and recommended phase II dose (RP2D ) in combination with CC-486. Phase II: determine the rate of best response [clinical improvement (CI), partial remission (PR), and complete remission (CR)] at week 24 of the combination treatment
Secondary outcome:
Time from first observation of response to relapse or death from any cause, whichever occurs first. Change in MF-associated symptoms by Cycle 6 from baseline as measured by the MF-SAF. Time from the first observation of best symptom response to first documented loss of symptom response. Percentage of subjects with a spleen response by palpation as defined by the IWG-MRT and ELN consensus report at the end of cycle 6 of the combination treatment as compared to baseline. Time from baseline to the first documented palpable response in spleen size by palpation according to the IWG-MRT and ELN consensus report. Time from the first observation of best spleen response to first documented loss of spleen response based on the IWG-MRT and ELN consensus report. Anemia response according to the IWG-MRT and ELN consensus report criteria. Time from the first treatment dose to disease progression, relapse or death from any cause, whichever occurs first. Time from the first treatment dose to death due to any cause. Transition to allogeneic SCT. Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, AEs, SAEs, ECGs, and vital signs. Analysis of incidence of subjects with a CTCAE Grade ≥3 of nausea, diarrhea, or vomiting, or occurrence of Encephalopathy, including Wernicke’s (confirmed by brain MRI or autopsy). Analysis of thiamine levels will be at screening, on Day 1 of the first 3 cycles, every third cycle thereafter, and at the EOT during the study.. Change in HRQoL from baseline measured monthly by the European Organization for Research and Treatment of Cancer Quality of Life C30 (EORTCQLQ-C30). Change in PRO from baseline measured monthly by the EQ- 5D-5L Questionnaires.

Study Design

Purpose:
Treatment
Allocation:
N/A (single arm study)
Control:
  • Uncontrolled/single arm
Phase:
I-II
Study type:
Interventional
Mechanism of allocation concealment:
No Entry
Blinding:
No
Assignment:
Single (group)
Sequence generation:
No Entry
Who is blinded:
No Entry

Recruitment

Recruitment Status:
Recruiting ongoing
Reason if recruiting stopped or withdrawn:
No Entry

Recruitment Locations

Recruitment countries:
  • Germany
Number of study centers:
Multicenter study
Recruitment location(s):
  • University medical center Medizinische Klinik III, Hämatologie, Onkologie, Palliativmedizin Rostock
  • University medical center Klinik für Hämatologie, Onkologie, Hämostasiologie und Palliativmedizin Minden
  • University medical center Klinik für Innere Medizin II, Abteilung für Hämatologie und Internistische Onkologie Jena
  • University medical center Klinik und Poliklinik für Innere Medizin C, Hämatologie und Onkologie, Transplantationszentrum, Palliativmedizin Greifswald
  • Medical center Klinik für Innere Medizin III Chemnitz
  • University medical center Klinik und Poliklinik für Innere Medizin IV Halle Saale
  • University medical center Klinik für Hämatologie und Internistische Onkologie Mainz
  • University medical center Medizinische Klinik IV Aachen
  • University medical center Nationales Centrum Tumorerkrankungen Dresden Dresden

Recruitment period and number of participants

Planned study start date:
No Entry
Actual study start date:
2022-11-03
Planned study completion date:
2027-03-31
Actual Study Completion Date:
No Entry
Target Sample Size:
44
Final Sample Size:
No Entry

Inclusion Criteria

Sex:
All
Minimum Age:
18 Years
Maximum Age:
no maximum age
Additional Inclusion Criteria:
- 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

- 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 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 - Officially and/or legally accommodated persons

Addresses

Primary Sponsor

Martin-Luther-Universität Halle-Wittenberg, Medizinische Fakultät
Magdeburger Str. 8
06112 Halle (Saale)
Germany
Telephone:
No Entry
Fax:
No Entry
Contact per E-Mail
URL:
No Entry
Investigator Sponsored/Initiated Trial (IST/IIT):
Yes

Contact for Scientific Queries

Universitätsklinikum Halle, Krukenberg Krebszentrum (KKH), Klinik und Poliklinik für Innere Medizin IV
Prof. Dr. med. Haifa-Kathrin Al-Ali
Ernst-Grube-Str. 40
06120 Halle (Saale)
Germany
Telephone:
+49-345-5574909
Fax:
+49-345-5577720
Contact per E-Mail
URL:
No Entry

Contact for Public Queries

Koordinierungszentrum für Klinische Studien, Medizinische Fakultät, Martin-Luther-Universität Halle-Wittenberg
Dr. Michael Richter
Kiefernweg 34
06120 Halle (Saale)
Germany
Telephone:
+49 345 5574907
Fax:
+49 345 557 5210
Contact per E-Mail
URL:
http://www.kks-halle.de/cms5/

Principal Investigator

Universitätsklinikum Halle, Krukenberg Krebszentrum (KKH), Klinik und Poliklinik für Innere Medizin IV
Prof. Dr. med. Haifa-Kathrin Al-Ali
Ernst-Grube-Str. 40
06120 Halle (Saale)
Germany
Telephone:
+49-345-5574909
Fax:
+49-345-5577720
Contact per E-Mail
URL:
No Entry

Sources of Monetary or Material Support

Commercial (pharmaceutical industry, medical engineering industry, etc.)

Celgene International 11 S.a.r.I.
2017 Boudry
Switzerland
Telephone:
No Entry
Fax:
No Entry
Contact per E-Mail
URL:
No Entry

Ethics Committee

Address Ethics Committee

Ethik-Kommission des Landes Sachsen-Anhalt
Kühnauer Straße 70
06846 Dessau
Germany
Telephone:
(+49)340-6501291
Fax:
(+49)340-6501199
Contact per E-Mail
URL:
No Entry

Vote of leading Ethics Committee

Date of ethics committee application:
2022-02-08
Ethics committee number:
22/030
Vote of the Ethics Committee:
Approved
Date of the vote:
2022-07-29

Further identification numbers

Other primary registry ID:
No Entry
EudraCT Number:
2021-003650-23
UTN (Universal Trial Number):
No Entry
EUDAMED Number:
No Entry

IPD - Individual Participant Data

Do you plan to make participant-related data (IPD) available to other researchers in an anonymized form?:
No
IPD Sharing Plan:
No Entry

Study protocol and other study documents

Study protocols:
No Entry
Study abstract:
No Entry
Other study documents:
No Entry
Background literature:
No Entry
Related DRKS studies:
No Entry

Publication of study results

Planned publication:
No Entry
Publikationen/Studienergebnisse:
No Entry
Date of first publication of study results:
No Entry
DRKS entry published for the first time with results:
No Entry

Basic reporting

Basic Reporting / Results tables:
No Entry
Brief summary of results:
No Entry