Phase II Study of Fedratinib and Nivolumab Combination in Patients with Myelofibrosis and Resistance or Suboptimal Response to JAK-inhibitor Treatment - The FRACTION Trial

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Pathological Conditions, Signs and Symptoms [C23]

Trial duration

23 Jun 2022 → 15 Jan 2026

Decision date (initial)

2024-10-24

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

BMS/Celgene

External identifiers

EU CT number

2024-513953-64-00

EudraCT number

2021-004757-23

ClinicalTrials.gov

NCT05393674

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To evaluate the clinical efficacy of Fedratinib and Nivolumab combination therapy in primary and secondary MF patients based on the consensus criteria of the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT), extended by the criterion RBC-transfusion independence (RBC-TI).

Secondary objectives 4

1. To evaluate the safety of combination therapy (Fedratinib and Nivolumab) in patients with primary and secondary MF.
2. To evaluate clinical benefit (defined as prolongation of RBC transfusion intervals by ≥50% compared to baseline in transfusion dependent patients or ≥1 g/dL Hb increase in the absence of RBC transfusion dependency and/or improvement of at least one MF-associated symptom according by a minimum of 50% and/or improvement of ≥2 MF-associated symptoms by a minimum of 25%), progression-free survival, response duration, disease burden (allelic ratio of the respective driver mutation and of high-risk mutations by next-generation sequencing [NGS]), fibrosis grade and overall survival.
3. To assess quality of life by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF, MPN10).
4. To assess adherence using a modified 8-item Adherence questionnaire.

Conditions and MedDRA coding

Primary and secondary Myelofibrosis

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Signed Informed Consent Form available
2. Patients* ≥18 years of age. *There are no data that indicate special gender distribution and the risk to be diagnosed with myelofibrosis (MF) does not depend on a patient’s gender. Therefore, patients will be enrolled in the study gender-independently.
3. Patients diagnosed with myelofibrosis (MF) according to the WHO 2008 or 2016 criteria, including primary (pre-fibrotic or overt) and secondary myelofibrosis.
4. Patients with an indication for therapy (either symptomatic patients with splenomegaly >11cm diameter and/or symptoms restricting their daily activity or patients with DIPSS int-2, or high risk or MIPSS70 int or high)
5. Patients with no response or suboptimal response to any JAK-inhibitor therapy (regarding persistence of symptoms, splenomegaly, cytopenia or hyperproliferation) defined either by • Persisting Splenomegaly >11cm total diameter • OR Persisting leukoerythroblastosis • OR Anemia <6.2 mmol/l (<10g/dl) • OR Elevated WBC (>11 Gpt/l) • OR Persisting general or constitutional symptoms (persistence is defined as less than 50% reduction to baseline when using the MPN10 TSS Score) • OR failure [secondary resistance] to JAK-inhibitor treatment as defined by IWG-MRT criteria.
6. ECOG performance status <3 at screening and adequate organ function
7. Reliable contraception should be maintained throughout the study and for 1 month after discontinuation of Fedratinib or 5 months after discontinuation of Nivolumab**
8. Subject must be willing to receive transfusion of blood products
9. Thiamine levels not below lower limit of normal (prior substitution is possible)
10. Normal nutritional status, as judged by the physician
11. Females of childbearing potential (FCBP) must undergo repetitive pregnancy testing (serum or urine) and pregnancy results must be negative.
12. Unless practicing complete abstinence from heterosexual intercourse, sexually active FCBP must agree to use adequate contraceptive methods (i.e. failure rate of < 1% per year).
13. Males (including those who have had a vasectomy) must use barrier contraception (condoms) when engaging in sexual activity with FCBP. Males must agree not to donate semen or sperm.

Exclusion criteria 22

1. Planned hematopoietic stem cell transplantation within 3 months and suitable donor available
2. >10% blasts in bone marrow smear (cytology) or >2x in blood smear within the screening phase or >20% blasts at any time in bone marrow or peripheral blood smears
3. Creatinine >2xN and Creatinine-Clearance <45ml/min; ALAT, ASAT & bilirubin >3xN (if MF impact on liver >5xN)
4. Baseline platelets count below 50 x 109/L and ANC < 1.0 x 109/L
5. Diagnosis of PV, ET (according to WHO 2016) or positive molecular test for BCR-ABL
6. Patients on ongoing medication for myelofibrosis including systemic corticosteroids (detailed list of permitted medications is provided in paragraph 9.1.10.4 and Appendix V). Use of steroids within 14 days prior to the first dose of study drug and until end of treatment is prohibited by patients.
7. Uncontrolled infection
8. Evidence of acute or chronic infection with hepatitis B, hepatitis C, human immunodeficiency virus (HIV) or tuberculosis
9. Current participation in any other interventional clinical study within 30 days before the first administration of the investigational product or at any time during the study, unless it is an observational (non-interventional) study, or during the follow-up period of an interventional study with last dose of investigational product ≥30 days prior first administration of investigational product within this study.
10. No consent for registration, storage and processing of the individual disease characteristics and course as well as information of the family physician about study participation
11. No consent for biobanking of patient’s biological specimens
12. Prior therapy with checkpoint-inhibitors
13. Vaccination within 4 weeks prior to treatment start
14. Hypersensitivity to the IMPs or to any of the excipients
15. History of or uncontrolled autoimmune disease such as autoimmune-hepatitis, -pneumonitis, -thyroiditis, chronic inflammatory bowel disease, multiple sclerosis, or rheumatologic diseases (including but not limited to systemic lupus and vasculitis)
16. History of malignancy except for i) adequately treated local basal cell or squamous cell carcinoma of the skin, ii) asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ≥ 1 year prior to randomization, or iii) any other cancer that has been in complete remission for ≥ 5 years
17. Secondary malignancy that limits survival to less than 6 months.
18. Drug or alcohol abuse within the last 6 months
19. Patients who cannot adhere to the Pregnancy Prevention Plan
20. Pregnant or breast-feeding females
21. Thiamine levels below normal limit despite supplementation
22. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG]

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Best response rate within 12 treatment cycles according to the IWG-MRT criteria (including complete remission, CR, partial remission, PR, clinical improvement, CI, stable disease, SD) 1, and red cell transfusion (RCT) independency according to Gale et al.

Secondary endpoints 12

1. Overall safety profile of Fedratinib and Nivolumab combination characterized by type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]), timing and relatedness of adverse events (AEs) and laboratory abnormalities observed during treatment, as well as cumulative incidence of leukemic transformation.
2. clinical benefit,
3. progression-free survival
4. duration of response
5. overall survival
6. reduction of disease burden
7. Quality of life assessed by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF, MPN10; Appendix VI), change in ECOG performance status (Appendix IV) from study entry to each visit where the variable is measured.
8. Adherence assessed by 8-item Adherence questionnaire.
9. Investigation of immune-cell expansion and immune-cell responses to checkpoint-inhibitor therapy at baseline (before first IMP dosing), after 6 months study treatment, and after 12 months study treatment (or at EOT).
10. Assessment of disease burden measured as allelic burden of the respective driver mutations (JAK2, CALR, MPL) at baseline (before first IMP dosing), after 6 months study treatment and after 12 months study treatment (or at EOT).
11. Assessment of clonal diversity and evolution by NGS-sequencing of a defined 32 gene panel at baseline (before first IMP dosing), after 6 months study treatment and after 12 months study treatment (or at EOT).
12. Assessment of bone marrow fibrosis by central histology (Professor Dombrowski, University Medicine Greifswald) at baseline before first IMP dosing (screening period) and after 12 months study treatment (or at EOT).

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Sponsor organisation

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Address

Steinbacher Hohl 2-26, Praunheim Praunheim

City

Frankfurt Am Main

Postcode

60488

Country

Germany

Scientific contact point

Organisation

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Contact name

Clinical Trial project manager

Public contact point

Organisation

Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH

Contact name

Clinical Trial project manager

Third parties 1

Locations

1 EU/EEA country · 7 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 8 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