Phase II Study of Fedratinib and Nivolumab Combination in Patients with Myelofibrosis and Resistance or Suboptimal Response to JAK-inhibitor Treatment - The FRACTION Trial
- Conditions
- Primary and secondary Myelofibrosis
- Registration Number
- 2024-513953-64-00
- Lead Sponsor
- Frankfurter Institut Fuer Klinische Krebsforschung IKF GmbH
- Brief Summary
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).
- Detailed Description
The FRACTION trial will evaluate the clinical efficacy of Fedratinib and Nivolumab combination therapy in patients with primary and secondary myelofibrosis 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).
Recruitment & Eligibility
- Status
- Ongoing, recruitment ended
- Sex
- Not specified
- Target Recruitment
- 30
Signed Informed Consent Form available
Normal nutritional status, as judged by the physician
Females of childbearing potential (FCBP) must undergo repetitive pregnancy testing (serum or urine) and pregnancy results must be negative.
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).
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.
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.
Patients diagnosed with myelofibrosis (MF) according to the WHO 2008 or 2016 criteria, including primary (pre-fibrotic or overt) and secondary myelofibrosis.
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)
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.
ECOG performance status <3 at screening and adequate organ function
Reliable contraception should be maintained throughout the study and for 1 month after discontinuation of Fedratinib or 5 months after discontinuation of Nivolumab**
Subject must be willing to receive transfusion of blood products
Thiamine levels not below lower limit of normal (prior substitution is possible)
Planned hematopoietic stem cell transplantation within 3 months and suitable donor available
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
No consent for biobanking of patient’s biological specimens
Prior therapy with checkpoint-inhibitors
Vaccination within 4 weeks prior to treatment start
Hypersensitivity to the IMPs or to any of the excipients
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)
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
Secondary malignancy that limits survival to less than 6 months.
Drug or alcohol abuse within the last 6 months
Patients who cannot adhere to the Pregnancy Prevention Plan
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
Pregnant or breast-feeding females
Thiamine levels below normal limit despite supplementation
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]
Creatinine >2xN and Creatinine-Clearance <45ml/min; ALAT, ASAT & bilirubin >3xN (if MF impact on liver >5xN)
Baseline platelets count below 50 x 109/L and ANC < 1.0 x 109/L
Diagnosis of PV, ET (according to WHO 2016) or positive molecular test for BCR-ABL
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.
Uncontrolled infection
Evidence of acute or chronic infection with hepatitis B, hepatitis C, human immunodeficiency virus (HIV) or tuberculosis
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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Primary Outcome Measures
Name Time Method 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. 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 Outcome Measures
Name Time Method 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. 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.
clinical benefit, clinical benefit,
progression-free survival progression-free survival
duration of response duration of response
overall survival overall survival
reduction of disease burden reduction of disease burden
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. 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.
Adherence assessed by 8-item Adherence questionnaire. Adherence assessed by 8-item Adherence questionnaire.
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). 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).
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). 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).
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). 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).
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). 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).
Trial Locations
- Locations (7)
Universitaetsklinikum Schleswig-Holstein AöR
🇩🇪Luebeck, Germany
Johannes Wesling Klinikum Minden
🇩🇪Minden, Germany
Universitaetsklinikum Ulm AöR
🇩🇪Ulm, Germany
Universitaetsklinikum Halle (Saale) AöR
🇩🇪Halle Saale, Germany
Universitaetsmedizin Greifswald KöR
🇩🇪Greifswald, Germany
Medical Center - University Of Freiburg
🇩🇪Freiburg Im Breisgau, Germany
Medizinische Hochschule Hannover
🇩🇪Hanover, Germany
Universitaetsklinikum Schleswig-Holstein AöR🇩🇪Luebeck, GermanyNikolas von BubnoffSite contact+4945150044151NikolasChristianCornelius.vonBubnoff@uksh.de