Study of Select Combinations in Adults With Myelofibrosis

Study Overview
=================
Brief Summary
-----------------
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, and MBG453 + NIS793 + spartalizumab)

Detailed Description
-----------------
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.

Official Title
-----------------
A Phase Ib, Multicenter, Open-label Dose Escalation and Expansion Platform Study of Select Combinations in Adult Patients With Myelofibrosis

Conditions
-----------------
PMF, Primary Myelofibrosis, Myelofibrosis, Post-Essential Thrombocythemia Myelofibrosis, Post-Polycythemia Vera Myelofibrosis

Intervention / Treatment
-----------------
* Drug: MBG453
* Drug: NIS793
* Drug: Spartalizumab
* Drug: Decitabine


Participation Criteria
=================
Eligibility Criteria
-----------------
Key inclusion criteria: Signed informed consent must be obtained prior to participation in the study. Male or female subjects must be ≥ 18 years of age at the time of signing the informed consent form (ICF). Subjects have a diagnosis of PMF as defined by the WHO criteria, or diagnosis of PET-MF or PPV-MF as defined by the IWG-MRT criteria (International Working Group for Myelofibrosis Research and Treatment). Subjects must have been treated with a JAK inhibitor for ≥3 months with inadequate efficacy response defined as <10% spleen volume reduction by MRI or <30% decrease from baseline in spleen length by physical examination or regrowth to these parameters following an initial response. And/or Treatment for ≥28 days complicated by either: Development of a red blood cell transfusion requirement (at least 2 units/month for 2 months); or Grade ≥3 AEs of thrombocytopenia, anemia, hematoma, and/or hemorrhage while on treatment with JAK inhibitor. Palpable spleen of at least 5 cm from the LCM to the point of greatest splenic protrusion or enlarged spleen volume of at least 450 cm3 per MRI or CT scan at baseline (an MRI/CT scan up to 8 weeks prior to first dose of study treatment can be accepted). Absolute neutrophil count (ANC) ≥ 1000/μL. Dose evaluation / Dose escalataion: Platelet count ≥ 75,000/μL without transfusion support Dose expansion: Platelet count ≥ 50,000/μL without transfusion support. Key exclusion criteria: Subjects with Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), or peripheral blasts ≥ 10 %, or AML transfromed from previous MPN. Subjects having received JAK inhibitors, systemic antineoplastic therapy (including unconjugated therapeutic antibodies, toxin immunoconjugates, and alpha-interferon) or any experimental therapy within 14 days or five half-lives, whichever is shorter, before the first dose of study treatment. Prior autologous or allogeneic stem cell transplant at any time. Candidate for allogenic hematopoietic stem cell transplantation at the time of enrolment. Splenic irradiation within 6 months prior to the first dose of study treatment. Prior splenectomy.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NIS793 + MBG453<br>treatment with NIS793 + MBG453 | Drug: MBG453<br>* Intravenous. 600mg. Every first day of a 21-day cycle, or on days 8 and 29 of a 42-day cycle (when in combination with Decitabine).<br>Drug: NIS793<br>* Intravenous. 2100mg. Every first day of a 21-day cycle, or on days 8 and 29 of a 42-day cycle (when in combination with Decitabine).<br>|
| Experimental: NIS793 + MBG453 + Spartalizumab<br>Treatment with NIS793 + MBG453 + Spartalizumab | Drug: MBG453<br>* Intravenous. 600mg. Every first day of a 21-day cycle, or on days 8 and 29 of a 42-day cycle (when in combination with Decitabine).<br>Drug: NIS793<br>* Intravenous. 2100mg. Every first day of a 21-day cycle, or on days 8 and 29 of a 42-day cycle (when in combination with Decitabine).<br>Drug: Spartalizumab<br>* Intravenous. 300mg. Every first day of a 21-day cycle<br>* Other names: PDR001;|
| Experimental: NIS793 + MBG453 + Decitabine<br>treatment with NIS793 + MBG453 + Decitabine | Drug: MBG453<br>* Intravenous. 600mg. Every first day of a 21-day cycle, or on days 8 and 29 of a 42-day cycle (when in combination with Decitabine).<br>Drug: NIS793<br>* Intravenous. 2100mg. Every first day of a 21-day cycle, or on days 8 and 29 of a 42-day cycle (when in combination with Decitabine).<br>Drug: Decitabine<br>* Intravenous. Starting dose: 5mg/m2 (dose cap at 20mg/m2). On days 1, 2 and 3 of a 42-day cycle<br>* Other names: Dacogen;|
| Experimental: NIS793<br>treatment with NIS793 | Drug: NIS793<br>* Intravenous. 2100mg. Every first day of a 21-day cycle, or on days 8 and 29 of a 42-day cycle (when in combination with Decitabine).<br>|
| Experimental: MBG453<br>treatment with MBG453 | Drug: MBG453<br>* Intravenous. 600mg. Every first day of a 21-day cycle, or on days 8 and 29 of a 42-day cycle (when in combination with Decitabine).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose limiting toxicities (DLT) | A dose-limiting toxicity (DLT) is defined as a clinically relevant adverse event or abnormal laboratory value where the relationship to study treatment cannot be ruled out, and which is unrelated to disease, disease progression, intercurrent illness, or concomitant medications that occurs within the DLT monitoring period and meets any of the criteria included in Table 6-4 (Criteria for defining dose-limiting toxicities). | 12 months | 
| Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs, and ECGs | Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs, and electrocardiograms (ECGs). A Serious adverse event (SAE) is defined as one of the following: Is fatal or life-threatening Results in persistent or significant disability/incapacity Constitutes a congenital anomaly/birth defect Is medically significant Requires inpatient hospitalization or prolongation of existing hospitalization. | 36 months | 
| Dose interruptions | Tolerability measured by the number of subjects who have interruptions of study treatment and reason for interruptions | 36 months | 
| Dose reductions | Tolerability measured by the number of subjects who have reductions of study treatment and reason for reductions | 36 months | 
| Dose intensity | Tolerability measured by the dose intensity of study drug, Relative Dose intensity for subjects with non-zero duration of exposure is computed as the ratio of dose intensity and planned dose intentity | 36 montths | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical benefit rate based on revised IWG-MRT (International Working Group Myelofibrosis Research & Treatment) criteria: complete response (CR), partial response (PR), stable disease, progressive disease (PD), Anemia response, Spleen response, relapse | Proportion of subjects achieving IWG-MRT (International Working Group for Myelofibrosis Research and Treatment) response criteria: Proportion of subjects with: complete response (CR) and partial response (PR), stable disease, progressive disease (PD). Proportion of subjects achieving Anemia response (anemia improvement of Hb ≥2.0 g/dL for transfusion independent subjects at baseline; or transfusion independence for transfusion dependent subjects at baseline). Proportion of subjects achieving spleen response (by palpation) from baseline or spleen volume reduction (by imaging) from baseline. Proportion of subjects experiencing relapse. | 36 months | 
| Proportion of subjects achieving improvement of Anemia | Proportion of subjects achieving improvement of Hb level of ≥ 1.5 g/dL from baseline | 36 months | 
| Progression-free survial time (PFS) | PFS is defined as the time from the date of start of treatment to the date of death by any cause or date of first documented progression as per IWG-MRT (International Working Group for Myelofibrosis Research and Treatment) criteria: Progressive splenomegaly as assessed by increasing spleen volume (by MRI/CT) of ≥ 25% from baseline. Accelerated phase defined by a circulating peripheral blood blast content of > 10% but <20% confirmed after 2 weeks. Deteriorating cytopenia (dCP) independent from treatment, defined for all patients by platelet count < 35 x10^9/L or neutrophil count < 0.75 x10^9/L that lasts for at least 4 weeks. Leukemic transformation defined by a peripheral blood blast content of ≥ 20% associated with an absolute blast count of ≥ 1x10^9/L that lasts for at least 2 weeks or a bone marrow blast count of ≥ 20%. | 36 months | 
| Duration of response | Time between the date of first documented response (as per the revised International Working Group for Myelofibrosis Research and Treatment IWG-MRT criteria) and the date of first documented progression or death. | 36 months | 
| Cmax (Maximum Concentration) | The maximum observed plasma, blood serum or other body fluid drug concentration | 36 months | 
| Tmax | Time to reach maximum plasma, blood serum or other body fluid drug concentration | 36 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Post-essential thrombocythemia myelofibrosis, PET-MF, MF, myeloproliferative neoplasms, thrombocythemia myelofibrosis, polycythemia vera, essential thrombocythemia, primary myelofibrosis, Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (PPV-MF), Post-Essential Thrombocythemia Myelofibrosis (PET-MF), primary myelofibrosis (PMF), osteomyelofibrosis, myeloproliferative neoplasm, chronic idiopathic myelofibrosis (cIMF), Angnogenic myeloid metaplasia, myelofibrosis with myeloid metaplasia (MMM)