An Efficacy and Safety Study of Fedratinib Compared to Best Available Therapy in Subjects With DIPSS-intermediate or High-risk Primary Myelofibrosis, Post-polycythemia Vera Myelofibrosis, or Post-essential Thrombocythemia Myelofibrosis and Previously Treated With Ruxolitinib

Myelofibrosis Clinical Trial

— FREEDOM2  

Official title:

A Phase 3, Multicenter, Open-label, Randomized Study to Evaluate the Efficacy and Safety of Fedratinib Compared to Best Available Therapy (BAT) in Subjects With DIPSS (Dynamic International Prognostic Scoring System)-Intermediate or High-risk Primary Myelofibrosis (PMF), Post-polycythemia Vera Myelofibrosis (Post-PV MF), or Post-essential Thrombocythemia Myelofibrosis (Post-ET MF) and Previously Treated With Ruxolitinib

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03952039
• Other study ID #: FEDR-MF-002
• Secondary ID: U1111-1223-29622
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: September 16, 2019
• Est. completion date: June 23, 2025

Study information

• Verified date: January 2024
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A Phase 3, multicenter, open-label, randomized study to evaluate the efficacy and safety of fedratinib compared to best available therapy (BAT) in subjects with DIPSS (Dynamic International Prognostic Scoring System)-intermediate or high-risk primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), or post-essential thrombocythemia myelofibrosis (post-ET MF) and previously treated with ruxolitinib. The primary objective of the study is to evaluate the percentage of subjects with at least 35% spleen volume reduction in the fedratinib and the BAT arms.

Description:

This Phase 3, multicenter, randomized, two-arm, open-label study will include subjects with intermediate or high-risk (as per the DIPSS score) primary myelofibrosis (PMF), postpolycythemia vera myelofibrosis (post-PV MF), or post-essential thrombocythemia myelofibrosis (post-ET MF). This study will be conducted in compliance with International Council for Harmonisation (ICH) Good Clinical Practices (GCPs).

Study design includes:

• A 28-day Screening Period

• 2:1 Randomization to fedratinib or best available therapy (BAT)

• Stratification at Randomization according to:

• Spleen size by palpation: < 15 cm below left costal margin (LCM) versus ≥ 15 cm below LCM

• Platelets ≥ 50 to < 100 x 109/L versus platelets ≥ 100 x 109/L

• Refractory or relapsed to ruxolitinib treatment versus intolerant to ruxolitinib treatment

• Study Treatment Period (time on study drug plus 30 days after last dose)

• Subjects are allowed to crossover from BAT to the fedratinib arm after the Cycle 6 response assessment or before the Cycle 6 response assessment in the event of a confirmed progression of splenomegaly by MRI/CT scan

• A Survival Follow-up Period for progression and survival

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 202
• Est. completion date: June 23, 2025
• Est. primary completion date: December 15, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Subject is at least 18 years of age at the time of signing the informed consent form (ICF)

2. Subject has an Eastern Cooperative Oncology Group (ECOG) Performance Score (PS) of 0, 1 or 2

3. Subject has diagnosis of primary myelofibrosis (PMF) according to the 2016 World Health Organization (WHO) criteria, or diagnosis of post-ET or post-PV myelofibrosis according to the IWG-MRT 2007 criteria, confirmed by the most recent local pathology report

4. Subject has a DIPSS Risk score of Intermediate-2 or High

5. Subject has a measurable splenomegaly during the screening period as demonstrated by spleen volume of = 450 cm3 by MRI or CT-scan and by palpable spleen measuring = 5 cm below the left costal margin

6. Subject has a measurable total symptoms score (= 1) as measured by the Myelofibrosis Symptom Assessment Form (MFSAF)

7. Subject has been previously exposed to ruxolitinib, and must meet at least one of the following criteria (a and/or b)

1. Treatment with ruxolitinib for = 3 months with inadequate efficacy response (refractory) defined as < 10% spleen volume reduction by MRI or < 30% decrease from baseline in spleen size by palpation or regrowth (relapsed) to these parameters following an initial response

2. Treatment with ruxolitinib for = 28 days complicated by any of the following (intolerant):

• Development of a red blood cell transfusion requirement (at least 2 units/month for 2 months) or

• Grade = 3 AEs of thrombocytopenia, anemia, hematoma, and/or hemorrhage while on treatment with ruxolitinib

8. Subject must have treatment-related toxicities from prior therapy resolved to Grade 1 or pretreatment baseline before start of last therapy prior to randomization

9. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted

10. Subject is willing and able to adhere to the study visit schedule and other protocol requirements

11. A female of childbearing potential (FCBP) must:

1. Have 2 negative pregnancy tests as verified by the Investigator during screening prior to starting study treatment. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence from heterosexual contact.

2. Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use and be able to comply with highly effective contraception without interruption, -14 days prior to starting investigational product, during the study treatment (including dose interruptions), and for 30 days after discontinuation of study treatment.

Note: A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).

12. A male subject must:

Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 30 days following investigational product discontinuation, or longer if required for each compound and/or by local regulations, even if he has undergone a successful vasectomy

Exclusion Criteria:

1. Any of the following laboratory abnormalities:

1. Platelets < 50 x 109/L

2. Absolute neutrophil count (ANC) < 1.0 x 109/L

3. White blood count (WBC) > 100 x 109/L

4. Myeloblasts = 5 % in peripheral blood

5. Estimated glomerular filtration rate < 30 mL/min/1.73 m2 (as per the Modification of Diet in Renal Disease [MDRD] formula)

6. Serum amylase or lipase > 1.5 x upper limit of normal (ULN)

7. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN)

8. 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

2. Subject is pregnant or lactating female

3. Subject with previous splenectomy

4. Subject with previous or planned hematopoietic cell transplant

5. Subject with prior history of encephalopathy, including Wernicke's (WE)

6. Subject with signs or symptoms of encephalopathy, including WE (eg, severe ataxia, ocular paralysis or cerebellar signs)

7. Subject with thiamine deficiency, defined as thiamine levels in whole blood below normal range according to the central laboratory and not demonstrated to be corrected prior to randomization

8. Subject with concomitant treatment with or use of pharmaceutical, herbal agents or food known to be strong or moderate inducers of Cytochrome P450 3A4 (CYP3A4), or dual CYP2C19 and CYP3A4 inhibitors

9. Subject on any chemotherapy, immunomodulatory drug therapy (eg, thalidomide, interferon-alpha), anagrelide, immunosuppressive therapy, systemic corticosteroids > 10 mg/day prednisone or equivalent. Subjects who have had prior exposure to hydroxyurea (eg, Hydrea) in the past may be enrolled into the study as long as it has not been administered within 14 days prior to randomization

10. Subject has received ruxolitinib within 14 days prior to randomization

11. Subject with previous exposure to Janus kinase (JAK) inhibitor(s) other than ruxolitinib treatment

12. Subject on treatment with aspirin with doses > 150 mg daily

13. Subject with major surgery within 28 days prior to randomization

14. Subject with diagnosis of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemochromatosis, non-alcoholic steatohepatitis)

15. 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 randomization. However, subject with the following history/concurrent conditions provided successfully treated may enroll: non-invasive skin cancer, in situ cervical cancer, carcinoma in situ of the breast, incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system), or is free of disease and on hormonal treatment only

16. Subject with uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4)

17. Subject with known human immunodeficiency virus (HIV), known active infectious Hepatitis B (HepB), and/or known active infectious Hepatitis C (HepC)

18. Subject with serious active infection

19. Subject with presence of any significant gastric or other disorder that would inhibit absorption of oral medication

20. Subject is unable to swallow capsule

21. Subject with any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study

22. Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study

23. Subject has any condition that confounds the ability to interpret data from the study

24. Subject with participation in any study of an investigational agent (drug, biologic, device) within 30 days prior to randomization

25. Subject with a life expectancy of less than 6 months

Related Conditions & MeSH terms

• Myelofibrosis
• Polycythemia
• Polycythemia Vera
• Post-Polycythemia Vera
• Primary Myelofibrosis
• Thrombocythemia, Essential
• Thrombocytosis

Intervention

Drug:
• FEDRATINIB
A potent and selective inhibitor of JAK2 kinase activity
• Best Available Therapy (BAT)
Best available therapy (BAT)

Locations

Country	Name	City	State
Australia	Local Institution - 101	Adelaide	South Australia
Australia	Local Institution - 105	Box Hill	Victoria
Australia	Local Institution - 103	Darlinghurst	New South Wales
Australia	Local Institution - 102	Frankston	Victoria
Australia	Local Institution - 100	Melbourne
Austria	Local Institution - 156	Graz
Austria	Local Institution - 154	Innsbruck
Austria	Local Institution - 155	Linz
Austria	Local Institution - 151	Salzburg
Austria	Local Institution - 150	Vienna
Austria	Local Institution - 153	Wels
Austria	Local Institution - 152	Wien
Belgium	Local Institution - 200	Brugge
Belgium	Local Institution - 202	Bruxelles
Belgium	Local Institution - 205	La Louvière-(Haine St-Paul)
Belgium	Local Institution - 201	Leuven
Belgium	Local Institution - 204	Liege
Belgium	Local Institution - 203	Yvoir
China	Local Institution - 555	Beijing
China	Local Institution - 550	Guangzhou, Guangdong
China	Local Institution - 553	Tianjin
China	Local Institution - 557	Zhengzhou
Czechia	Local Institution - 700	Brno
Czechia	Local Institution - 702	Ostrava-Poruba
Czechia	Local Institution - 701	Prague 2
France	Local Institution - 255	Angers
France	Local Institution - 256	Brest
France	Local Institution - 254	Lens Cedex
France	Local Institution - 259	Lille
France	Local Institution - 260	Nice Cedex 3
France	Local Institution - 250	Nimes Cedex 9
France	Local Institution - 252	Paris
France	Local Institution - 258	Pessac
France	Local Institution - 257	Pierre-Benite
France	Local Institution - 261	Poitiers Cedex
France	Local Institution - 251	Strasbourg
France	Local Institution - 253	Toulouse Cedex 9
Germany	Local Institution - 302	Aachen
Germany	Local Institution - 308	Frankfurt am Main
Germany	Local Institution - 306	Halle
Germany	Local Institution - 303	Jena
Germany	Local Institution - 307	Magdeburg
Germany	Local Institution - 301	Mannheim
Germany	Local Institution - 304	Minden
Germany	Local Institution - 305	Ulm
Hungary	Local Institution - 600	Budapest
Hungary	Local Institution - 601	Györ
Hungary	Local Institution - 602	Kaposvar
Hungary	Local Institution - 604	Nyiregyhaza
Hungary	Local Institution - 603	Szeged
Ireland	Local Institution - 751	Cork
Ireland	Local Institution - 750	Dublin
Ireland	Local Institution - 752	Dublin
Italy	Local Institution - 353	Bologna
Italy	Local Institution - 363	Brescia
Italy	Local Institution - 354	Catania
Italy	Local Institution - 350	Firenze
Italy	Local Institution - 358	Milano
Italy	Local Institution - 362	Naples
Italy	Local Institution - 357	Pavia
Italy	Local Institution - 356	Roma
Italy	Local Institution - 359	Roma
Italy	Local Institution - 361	Roma
Italy	Local Institution - 355	Torino
Italy	Local Institution - 360	Udine
Italy	Local Institution - 352	Varese
Italy	Local Institution - 364	Verona
Korea, Republic of	Local Institution - 900	Seongnam-si
Korea, Republic of	Local Institution - 901	Seoul
Korea, Republic of	Local Institution - 902	Seoul
Korea, Republic of	Local Institution - 903	Seoul
Korea, Republic of	Local Institution - 904	Seoul
Korea, Republic of	Local Institution - 905	Seoul
Netherlands	Local Institution - 402	Maastricht
Netherlands	Local Institution - 400	Nijmegen
Poland	Local Institution - 803	Poznan
Poland	Local Institution - 801	Warszawa
Poland	Local Institution - 802	Wroclaw
Russian Federation	Local Institution - 851	Moscow
Russian Federation	Local Institution - 853	Moscow
Russian Federation	Local Institution - 855	Moscow
Russian Federation	Local Institution - 857	Novosibirsk
Russian Federation	Local Institution - 852	Saint Petersburg
Russian Federation	Local Institution - 854	Saint-Petersburg
Russian Federation	Local Institution - 850	St Petersburg
Russian Federation	Local Institution - 859	Vladikavkaz
Spain	Local Institution - 451	Alicante
Spain	Local Institution - 452	Badalona (Barcelona)
Spain	Local Institution - 458	Barakaldo
Spain	Local Institution - 450	Barcelona
Spain	Local Institution - 462	Gerona
Spain	Local Institution - 461	Las Palmas de Gran Canaria
Spain	Local Institution - 453	Madrid
Spain	Local Institution - 459	Madrid
Spain	Local Institution - 457	Malaga
Spain	Local Institution - 454	Murcia
Spain	Local Institution - 455	Salamanca
Spain	Local Institution - 463	Santa Cruz de Tenerife
Spain	Local Institution - 460	Santiago de Compostela
Spain	Local Institution - 456	Valencia
United Kingdom	Local Institution - 502	Birmingham
United Kingdom	Local Institution - 503	Boston
United Kingdom	Local Institution - 501	London
United Kingdom	Local Institution - 505	London
United Kingdom	Local Institution - 504	Manchester	Lancashire
United Kingdom	Local Institution - 506	Nottingham	Nottinghamshire
United Kingdom	Local Institution - 500	Oxford

Sponsors (2)

Lead Sponsor	Collaborator
Celgene	Impact Biomedicines, Inc., a wholly owned subsidiary of Celgene Corporation

Countries where clinical trial is conducted

Australia,  Austria,  Belgium,  China,  Czechia,  France,  Germany,  Hungary,  Ireland,  Italy,  Korea, Republic of,  Netherlands,  Poland,  Russian Federation,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Spleen Volume Response Rate (RR)	Percentage of participants who have = 35% spleen volume reduction (SVR) at end of cycle 6; A Cochran-Mantel-Haenszel (CMH) test to adjust for planned stratification factors (spleen size by palpation, platelet counts and refractory/relapsed or intolerance to ruxolitinib treatment).; The RRs and 95% confidence intervals (CI) will be provided for each arm as well as for the difference in RRs and 95% confidence interval of the difference for fedratinib to BAT.	From Screening to end of Cycle 6 (1 cycle = 28 days), approximately 196 days
Secondary	Symptom Response Rate (SRR)	Percentage of participants with = 50% reduction in total symptom scores measured by Myelofibrosis Symptom Assessment Form (MFSAF) 4.0 at end of cycle 6.; Subjects with a missing TSS at the end of cycle 6 or who had disease progression before the end of the cycle 6 will be considered non-responders.; MFSAF measures the sum of 7 symptoms on a scale from 0 to 10 (0 being absent and 10 being the worst imagineable). The lower the score the better.; A Cochran-Mantel-Haenszel (CMH) test to adjust for planned stratification factors (spleen size by palpation, platelet counts and refractory/relapsed or intolerance to ruxolitinib treatment).; The SRRs and 95% confidence intervals (CI) will be provided for each arm as well as for the difference in SRRs and 95% confidence interval of the difference for fedratinib to BAT.	From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
Secondary	Spleen Volume Response Rate (RR25)	Percentage of participants who have = 25% spleen volume reduction (SVR) at end of cycle 6; A Cochran-Mantel-Haenszel (CMH) test to adjust for planned stratification factors (spleen size by palpation, platelet counts and refractory/relapsed or intolerance to ruxolitinib treatment).; The RRs and 95% confidence intervals (CI) will be provided for each arm as well as for the difference in RRs and 95% confidence interval of the difference for fedratinib to BAT.	From Screening to end of Cycle 6 (1 cycle = 28 days), approximately 196 days
Secondary	Number of Participants With All Grade Treatment Emergent Adverse Events (AEs) and Grade 3 to 4 Treatment Emergent AEs	Number of participants with all grade adverse events (AEs) and grade 3 to 4 AEs	From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
Secondary	Number of Participants With Hematology Laboratory Abnormalities	Number of participants with hematology laboratory abnormalities in the following parameters: hemoglobin (decreased), leukocytes (increase and decrease), lymphocytes (decreased), neutrophils (segmented and band form decreased), Platelets (decreased).	From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
Secondary	Spleen Response Rate by Palpation (RRP)	Spleen response rate by palpation is the percentage of participants at the end of cycle 6 with a spleen response according to the IWG-MRT 2013 criteria.; A baseline splenomegaly that is palpable at 5-10 cm, below the LCM, becomes not palpable** or A baseline splenomegaly that is palpable at > 10 cm, below the LCM, decreases by = 50%**; Participants with a missing spleen size assessment at the end of cycle 6 including those who meet the criteria for progression of splenomegaly before end of cycle 6 will be considered not to be responders.	From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
Secondary	Durability of Spleen Volume Response (DR)	Durability of spleen volume response (DR) by MRI/CT is defined as the date from the first documented spleen response (ie, = 35% reduction in spleen volume) to the date of subsequent progressive disease (PD) in spleen volume per the IWG-MRT 2013 criteria or death, whichever is earlier. In the absence of an event before the analysis is performed, the DR will be censored at the date of the last valid assessment performed before the analysis performed date.	From baseline to end of treatment visit, Approximately on average 53 weeks up to 151 weeks.
Secondary	Durability of Spleen Response by Palpation (DRP)	Durability of spleen response by palpation (DRP) is defined as time from the date of the first documented palpable spleen response, according to the IWG-MRT 2013 to the date of the subsequent PD in spleen size according to the IWG-MRT 2013 or death, whichever is earlier. Durability of spleen response by palpation according to the IWG-MRT 2013 criteria will be calculated for subjects that have an enlarged spleen at baseline (= 5 cm below LCM), and that have a spleen response by palpation. In the absence of an event before the analysis is performed, the DRP will be censored at the date of the last valid assessment performed before the analysis performed date.	From baseline to end of treatment visit, Approximately on average 53 weeks up to 151 weeks.
Secondary	Durability of Symptoms Response (DSR)	The DSR is defined as time from the first documented response in TSS (ie, reduction in TSS = 50%) measured by MFSAF version 4.0 to the first documented TSS reduction < 50%. In the absence of TSS reduction < 50% before the analysis performed, the DSR will be censored at the date of the last valid assessment performed before the analysis performed date.	From baseline to end of treatment visit, Approximately on average 53 weeks up to 151 weeks.
Secondary	Assessment of the Effectiveness of Risk Mitigation Strategy for =3 Grade Gastrointestinal Adverse Events and Any Grade Wernickes Encephalopathy	Number of participants with a CTCAE Grade =3 of nausea, diarrhea, or vomiting and any grade wernickes encephalopathy.	From Screening to end of Cycle 6 (1 cycle = 28 days), approximately 196 days
Secondary	Number of Participants With Thiamine Levels Below the Lower Limit of Normal	Number of participants with thiamine levels below the lower limit of normal	From Cycle 1 Dose 1 to end of Cycle 6, approximately 168 days
Secondary	Mean Change in EORTC QOL-C30 at Cycle 7 Day 1 as Compared With Baseline	QLQ-C30 - The EORTC QLQ-C30 was developed to assess the quality of life of cancer patients. It consists of 30 items classified into 15 domains including 5 functional subscales (physical functioning, role functioning, emotional functioning, cognitive functioning, and social functioning); 3 multi-item symptom subscales (fatigue, nausea/vomiting, and pain); a global QOL subscale; and 6 single items addressing various symptoms and perceived financial impact. Scores vary from 0 (worst) to 100 (best) for the functional dimensions and GHS, and from 0 (best) to 100 (worst) for the symptom dimensions.	from the start of cycle 1 to cycle 7 day 1 approximately 170 days.
Secondary	Mean Change From Baseline in EQ-5D-5L Utility Index Score	EQ-5D-5L - The EQ-5D-5L is a generic, self-administered preference-based measure of health. The five dimensions covered by the EQ-5D-5L include mobility, self-care, pain, usual activities, and anxiety/depression and is converted into a single summary index that can range from -0.594 to 1.0, with a score of 0 indicating death, 1.00 indicating "full health," and negative scores reflecting states perceived to be worse than death. Respondent's self-rated health on a vertical, 0 to 100 scale where 100 = "Best imaginable health state" and 0 = "Worst imaginable health state"	from the start of cycle 1 to cycle 7 day 1 approximately 170 days.
Secondary	Time to Spleen and Disease Progression Free Survival (SDPFS)	Time from randomization to death due to any reason or disease progression (modified IWG-MRT 2013 including = 25% increase in spleen volume by MRI/CT).	From randomization to the End of Survival Follow-up
Secondary	Overall Survival	Time from randomization to death due to any reason	From Randomization to the end of Survival Follow Up

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