The purpose of this study is to investigate the safety, pharmacokinetics (PK) and
preliminary efficacy of both the combination of MBG453 and NIS793 with or without
decitabine or spartalizumab as well as single agent MBG453 and/or NIS793 single agent in
myelofibrosis (MF) subjects post treatment with a Janus Kinase (JAK) inhibitor.
In this study, combination therapies with novel agents including immune therapy will
focus on determining the promising combinations that provide acceptable safety and
efficacy independent of JAK inhibitors. Immune therapy combinations, such as MBG453 in
combination with NIS793, might offer the potential to target MF across genetic
heterogeneity.
The primary objective of this study is to characterize the safety, tolerability and
recomended dose for each treatment combination (MBG453 + NIS793, MBG453 + NIS793 +
decitabine, MBG453 + NIS793 + spartalizumab).
Secondary Objectives are: to evaluate the efficacy based on the revised International
Working Group for Myelofibrosis Research and Treatment (IWG-MRT) response criteria, to
evaluate the effect of each combination treatment in delaying progression of MF and
estimate time to progression free survival (PFS) event, and to characterize the PK
profile of each treatment arm Study is designed as a Phase Ib, multi center, open label
study with multiple treatment arms. The study is comprised of a dose
evaluation/escalation part and a dose expansion part.
MBG453 in combination with NIS793 will be explored as the initial backbone. As the study
progresses and based on emerging clinical data collected from this study, Novartis, in
agreement with the study Investigators will decide whether or not:
- To proceed with any treatment arm that reaches recommended dose(s) to explore
further the safety, tolerability, and anti-tumor activity in the dose expansion
part.
- To add a third partner to comprise a triplet treatment arm in the dose
evaluation/escalation part (such as Treatment Arm 2 with decitabine or Treatment Arm
3 with spartalizumab.
- To explore MBG453 single agent (Treatment Arm 4) and/or NIS793 single agent
(Treatment Arm 5) in the dose expansion part in order to assess the single agent
contributions to efficacy.
The patient population will include male or female adults (age 18 or over) with a
confirmed diagnosis of primary myelofibrosis (PMF) as defined by the World Health
Organization (WHO) criteria, or Post-Polycythemia Vera Myelofibrosis (PPV-MF), or
Post-Essential Thrombocythemia Myelofibrosis (PET-MF) based on the revised IWG-MRT)
criteria, irrespective of JAK2 mutation status and must have been treated with a JAK
inhibitor for at least 28 days but no more than 6 months and experienced according to the
Investigator suboptimal response defined by loss of spleen response, or worsening of
symptoms or discontinuation due to adverse events (AE).
Data analysis: the primary objective of the study is to characterize the safety and
tolerability of each combination and identify the recommended dose. The primary analysis
will be based on a Bayesian Hierarchical Logistic Regression Model (BHLRM) and summaries
of other safety, tolerabitliy endpoints. Efficacy will be assessed based on IWG-MRT. The
study data will be analyzed and reported based on all patients' data up to the time when
80% of the patients have completed the follow-up for disease progression or discontinued
the study for any reason, and all patients have completed treatment and the safety
follow-up period.
