ET
The primary objective for Part 1 (Dose Escalation) is to characterize safety and to determine the putative RP2D(s) and optimal dosing schedule(s) of JNJ-88549968 in monotherapy for ET and MF and in combination with ruxolitinib or momelotinib for MF only. For Part 2 (Cohort Expansion), this clinical study will further characterize the safety of JNJ-88549968 at the putative RP2D(s), in monotherapy for ET and MF and in combination with ruxolitinib or momelotinib for MF only. The secondary objectives will be to characterize the PK, assess immunogenicity, and evaluate the preliminary clinical activity of JNJ-88549968 in participants with advanced CALRmut MPN, either alone or in combination with ruxolitinib or momelotinib. In MF, participants who are ineligible for JAK inhibition or who have become resistant to or intolerant of therapy will be evaluated using JNJ-88549968 monotherapy. JNJ-88549968 will be used in combination with ruxolitinib or momelotinib for participants who are JAK inhibitor-eligible and who have not received any JAK inhibitors. In ET, participants who are intolerant of or resistant to at least 2 lines of therapy will be evaluated and JNJ-88549968 will be used as monotherapy.
MF
The primary objective for Part 1 (Dose Escalation) is to characterize safety and to determine the putative RP2D(s) and optimal dosing schedule(s) of JNJ-88549968 in monotherapy for ET and MF and in combination with ruxolitinib or momelotinib for MF only. For Part 2 (Cohort Expansion), this clinical study will further characterize the safety of JNJ-88549968 at the putative RP2D(s), in monotherapy for ET and MF and in combination with ruxolitinib or momelotinib for MF only. The secondary objectives will be to characterize the PK, assess immunogenicity, and evaluate the preliminary clinical activity of JNJ-88549968 in participants with advanced CALRmut MPN, either alone or in combination with ruxolitinib or momelotinib. In MF, participants who are ineligible for JAK inhibition or who have become resistant to or intolerant of therapy will be evaluated using JNJ-88549968 monotherapy. JNJ-88549968 will be used in combination with ruxolitinib or momelotinib for participants who are JAK inhibitor-eligible and who have not received any JAK inhibitors. In ET, participants who are intolerant of or resistant to at least 2 lines of therapy will be evaluated and JNJ-88549968 will be used as monotherapy.
Primary Objective
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
• To evaluate the safety of combination therapy (Fedratinib and Nivolumab) in patients with primary and secondary MF.
• 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.
• To assess quality of life by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF, MPN10).
• To assess adherence using a 8-item Adherence questionnaire.
The study is a phase 3 study of navtemadlin as add-on therapy to standard of care ruxolitinib in patients with MF who have a suboptimal response to ruxolitinib. The study includes a ≥ 18 week but < 25-week run-in period in which patients receive ruxolitinib monotherapy to identify a homogenous population of suboptimal responders to standard of care ruxolitinib treatment. At the end of the run-in period, patients assessed as suboptimal responders to ruxolitinib and who meet the eligibility criteria will be randomized in a double-blind, placebo-controlled manner to receive either navtemadlin or placebo as add-on therapy to their continuous ruxolitinib treatment.
This study has two goals:
1. Adequately isolate the contribution of add-on navtemadlin in the setting of continuous ruxolitinib use.
2. Demonstrate that this contribution is clinically meaningful to the suboptimal responder.
Pilot studies
To date, there have been no randomized intervention studies on the effects of physical exercise in MPN. The Department of Hematology at MHH operates a very large outpatient clinic for patients with MPN. Therefore, in a collaborative effort between the departments, we would like to conduct a pilot study to investigate whether physical exercise can improve subjective quality of life (QOL). We also aim to determine which outcomes provide the best possible information on this topic. The objective of the study is to implement an individually tailored physical exercise program with online monitoring for patients with MPN and to measure its effects on quality of life and physical endurance.