Phase II Evaluation of Fedratinib and Nivolumab in Myelofibrosis Patients with JAK-Inhibitor Resistance or Suboptimal Response
- Trial ID
- 2024-513953-64-00
- Protocol
- FRACTION_2021
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase II study is to evaluate the **clinical efficacy** of the combination therapy of Fedratinib and Nivolumab in patients with primary and secondary **Myelofibrosis** (MF) who exhibit resistance or suboptimal response to JAK-inhibitor treatment. This evaluation is based on the consensus criteria of the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT), with an extension to include the criterion of red blood cell transfusion independence (RBC-TI). The clinical relevance of this objective lies in its potential to offer an alternative therapeutic strategy for patients with limited treatment options due to resistance or inadequate response to existing therapies.
Secondary objectives include:
- Evaluating the safety of the combination therapy in patients with primary and secondary MF.
- Assessing clinical benefits such as prolongation of red blood cell transfusion intervals, increase in hemoglobin levels, improvement in MF-associated symptoms, progression-free survival, response duration, disease burden, fibrosis grade, and overall survival.
- Assessing quality of life using the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF, MPN10).
- Evaluating adherence using a modified 8-item Adherence questionnaire.
Participants
The clinical trial involves participants diagnosed with **primary and secondary Myelofibrosis**. The study population includes both male and female subjects, aged 18 years and older, without any specific gender distribution bias. Participants are required to have a normal nutritional status and an **ECOG performance status** of less than 3 at screening, indicating a generally stable health condition. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria include individuals with an indication for therapy, such as symptomatic patients with significant splenomegaly or those with high-risk scores according to DIPSS or MIPSS70. Participants must have shown no response or a suboptimal response to previous JAK-inhibitor therapy. Lifestyle considerations include the requirement for reliable contraception throughout the study and for a specified period after discontinuation of the study drugs. The trial population is selected based on these criteria, ensuring that participants are suitable for evaluating the efficacy of the combination therapy of Fedratinib and Nivolumab.
Plans and Procedures
The clinical trial is designed as an **interventional, non-randomized, single-arm, open-label, multi-center phase II study** to evaluate the clinical efficacy of a combination therapy involving **Fedratinib** and **Nivolumab** in patients with primary and secondary **myelofibrosis** who exhibit resistance or suboptimal response to JAK-inhibitor treatment. The trial aims to assess the best response rate within 12 treatment cycles according to the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria, including complete remission, partial remission, clinical improvement, stable disease, and red cell transfusion independence. The trial is expected to conclude by February 27, 2026, with recruitment having commenced on July 5, 2022.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of myelofibrosis, and previous response to JAK-inhibitor therapy. The trial will include regular follow-up visits to monitor the safety profile of the combination therapy, characterized by the type, frequency, and severity of adverse events, as well as laboratory abnormalities. These visits will also assess clinical benefits, progression-free survival, duration of response, overall survival, and quality of life using the Myeloproliferative Neoplasm Symptom Assessment Form. The end-of-study visit will evaluate the overall outcomes and any long-term effects of the treatment.
The expected length of participant involvement is up to 42 weeks, with conditions for early termination including significant adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. Participants are required to maintain reliable contraception throughout the study and for a specified period after discontinuation of the investigational products. The trial will also investigate immune-cell responses to checkpoint-inhibitor therapy and assess disease burden through various molecular and histological analyses at baseline, after 6 months, and at the end of treatment.
Treatment
The clinical trial involves the administration of two experimental medications: **Nivolumab** and **Fedratinib**. **Nivolumab**, marketed under the name OPDIVO, is provided as a 10 mg/mL concentrate for solution for infusion. It is administered via **intravenous infusion**. The maximum daily dose of Nivolumab is 240 mg, with a total maximum dose of 21,360 mg over a treatment period of 42 days. The pharmaceutical form is a solution for infusion, and the active substance is a protein of other origin. The study-specific label is applied to the product, and it is not a pediatric formulation. Participant compliance with the dosing schedule is monitored throughout the trial.
**Fedratinib**, marketed as Inrebic, is provided in the form of 100 mg hard capsules. It is administered **orally**. The maximum daily dose of Fedratinib is 400 mg, with a total maximum dose of 255,500 mg over a treatment period of 42 days. The active substance is of chemical origin. Similar to Nivolumab, Fedratinib is labeled specifically for the study and is not intended for pediatric use. The trial aims to evaluate the combination therapy of Fedratinib and Nivolumab in patients with **myelofibrosis** who exhibit resistance or suboptimal response to JAK-inhibitor treatment. Compliance with the oral dosing schedule is also monitored to ensure adherence to the treatment protocol.
Efficacy
Efficacy in this clinical trial will be assessed using a combination of primary and secondary endpoints. The primary endpoint is the best response rate within 12 treatment cycles, evaluated according to the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria. This includes assessments of complete remission (CR), partial remission (PR), clinical improvement (CI), stable disease (SD), and red cell transfusion (RCT) independence as defined by Gale et al.
Secondary endpoints will provide a comprehensive evaluation of the treatment's impact. These include the overall safety profile of the combination therapy, characterized by the type, frequency, and severity of adverse events, as well as the cumulative incidence of leukemic transformation. Additional secondary endpoints include clinical benefit, progression-free survival, duration of response, overall survival, and reduction of disease burden. Quality of life will be assessed using the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF, MPN10), and changes in ECOG performance status will be monitored from study entry to each visit.
Further assessments involve the investigation of immune-cell expansion and responses to checkpoint-inhibitor therapy at baseline, after 6 months, and after 12 months of study treatment. Disease burden will be measured by the allelic burden of driver mutations (JAK2, CALR, MPL) at similar timepoints. Clonal diversity and evolution will be evaluated through NGS-sequencing of a defined 32 gene panel, and bone marrow fibrosis will be assessed by central histology at baseline and after 12 months of treatment.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed Informed Consent Form available
- 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)
- 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.
Exclusion Criteria
- Planned hematopoietic stem cell transplantation within 3 months and suitable donor available
- >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
- 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.
- 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
- 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]
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Not Recruiting | 05 Jul 2022 | 30 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
OPDIVO 10 mg/mL concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 240 | 42 | PRD2941375 |
Inrebic 100 mg hard capsules | Test | HARD CAPSULES | ORAL | 400 | 42 | PRD9247882 |