Fedratinib in Combination With Nivolumab

A Phase II Study of Fedratinib and Nivolumab Combination in Patients With Myelofibrosis and Resistance or Suboptimal Response to JAK-inhibitor Treatment

A multicenter, open-label, single arm, phase II study investigating the clinical efficacy of Fedratinib and Nivolumab combination in patients with myelofibrosis and resistance or suboptimal response to JAK-inhibitor treatment

Study Overview

• Status: Recruiting
• Conditions: Primary Myelofibrosis; Secondary Myelofibrosis
• Intervention / Treatment: Drug: Fedratinib Oral Capsule [Inrebic]; Drug: Nivolumab

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).

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Florian Heidel, Prof. Dr.; Phone Number: 3020 (+49) 511 532; Email: heidel.florian@mh-hannover.de
• Study Contact Backup: Name: Luisa Wohn; Email: wohn.luisa@ikf-khnw.de

Study Locations

• Germany
  • Berlin, Germany
    • Recruiting
    • Charité
    • Contact: Philipp le Coutre, Prof. Dr.
  • Freiburg, Germany
    • Recruiting
    • Universitätsklinikum Freiburg
    • Contact: Heiko Becker, Prof. Dr.
  • Greifswald, Germany
    • Recruiting
    • University Medicine Greifswald
    • Contact: Florian Heidel, Prof. Dr.
  • Halle (Saale), Germany
    • Recruiting
    • Universitatsklinikum Halle (Saale)
    • Contact: Haifa Kathrin Al-Ali, Dr.
  • Hannover, Germany
    • Recruiting
    • Medizinische Hochschule
    • Contact: Florian Heidel, Prof. Dr.
  • Lübeck, Germany
    • Recruiting
    • Universitätsklinikum Schleswig-Holstein
    • Contact: Nikolas von Bubnoff, Prof. Dr.
  • Minden, Germany
    • Recruiting
    • Johannes Wesling Klinikum
    • Contact: Martin Griesshammer, Prof. Dr.
  • Ulm, Germany
    • Recruiting
    • Uniklinik Ulm
    • Contact: Konstanze Döhner, Prof. Dr.
  • Hessen
    • Frankfurt am Main, Hessen, Germany
      • Recruiting
      • Krankenhaus Nordwest
      • Contact: Thorsten Götze, Prof. Dr.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Signed Informed Consent Form available and patient willing and able to adhere to the study visit schedule and other protocol requirements.
2. Patients* ≥18 years of age
3. 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
   • Persisting leukoerythroblastosis
   • Anemia <6.2 mmol/l (<10g/dl)
   • Elevated WBC (>11 Gpt/l)
   • 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:

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 >2xULN and Creatinine-Clearance <45ml/min; ALAT, ASAT & bilirubin >3xULN (if MF impact on liver >5xULN)
4. Baseline platelets count below 50 x 10^9/L and ANC < 1.0 x 10^9/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]

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental; Fedratinib (Cycle 1: Run-in-Phase with 400 mg QD for 4 weeks, Cycle 2-12: 400 mg QD, Dose modifications will be allowed based on observed toxicity to a 300 mg or a 200 mg daily dose) + Nivolumab (Cycle 2-12: 240 mg, i.v., q2w) Patients will receive study treatment until loss of response, death or study discontinuation for other reasons.	Drug: Fedratinib Oral Capsule [Inrebic]; 400 mg once daily p.o. from cycle 1-n, dose adjustment will be made according to the protocol; Drug: Nivolumab; 240 mg every 2 weeks i.v. from cycle 2-n

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best response rate within 12 treatment cycles	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.)	12 months after therapy start.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety: Incidence and severity of adverse events according to CTC criteria	Incidence and severity of adverse events according to CTC criteria	From informed consent until 100 days after last study drug
Safety: Timing of adverse events according to CTC criteria	Timing of adverse events according to CTC criteria	From informed consent until 100 days after last study drug
Safety: Incidence of Laboratory abnormalities	Incidence of laboratory abnormalities including timing and relatedness.	From informed consent until 100 days after last study drug
Safety: leukemic transformation	Cumulative incidence of leukemic transformation	From informed consent until 100 days after last study drug
Clinical benefit	Proportion of patients with clinical benefit defined as stable disease (SD) plus hematologic improvement or stable disease (SD) plus improvement of MF-associated symptoms	3.5 years
Efficacy: PFS	Progression-free survival	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 42 months
Efficacy: Duration of response	Time from first response including RBC-TI, CI, PR and CR (Appendix III) to date of loss of response. Times of patients without loss of response are censored at last tumor assessment.	3.5 years
Efficacy: Overall survival	Time from study entry to the last date known to be alive or death. Survival times of patients alive at last follow-up are censored.	3.5 years
Efficacy: Disease burden	Change of disease burden assessed by allelic ratio of the respective driver mutation and of high-risk mutations by next-generation sequencing [NGS]	3.5 years

Collaborators and Investigators

• Sponsor: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
• Collaborators: Celgene International II S.á.r.l.; Prof. F. Heidel, MH Hannover
• Investigators: Study Director: Salah-Eddin Al-Batran, Prof. Dr., Institut für Klinische Krebsforschung IKF GmbH

Study record dates

Study Major Dates

• Study Start (Actual): June 14, 2022
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: May 17, 2022
• First Submitted That Met QC Criteria: May 25, 2022
• First Posted (Actual): May 26, 2022

Study Record Updates

• Last Update Posted (Estimated): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 5, 2024
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Nivolumab; MF; Fedratinib; JAK-inhibitor
• Additional Relevant MeSH Terms: Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Primary Myelofibrosis; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: FRACTION_2021

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: No IPD will be shared

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No