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Palifermin once daily at a dose of 60 mg/kg/day for 3 days before the start of the conditioning regimen and then for 3 consecutive days starting on the day of transplantation (days 0 to day +2 inclusively).

Placebo at a dose of 1.2 mL (saline 0,9%) once daily for 3 days before the start of the conditioning regimen and then for 3 consecutive days starting on the day of transplantation (days 0 to day +2 inclusively).

Palifermin

Placebo

Ruth Seggewiss, MD

This is a double blind, placebo controlled clinical trial, where patients with an advanced form of blood cancer are treated with haploidentical allogeneic peripheral blood progenitor cell (PBPC) transplant after which they are randomised to receive either placebo or a keratinocyte growth factor (Palifermin or Kepivance®).

The function of Kepivance® is to stimulate the growth of epithelial cells. This drug has also been suggested to have an ability to help improve the reconstitution, or development, of the immune system after the transplantation.

The hypothesis is that the patients T-cell dependent humoral immune response to recall antigen (PrevenarTM) will be higher in in palifermin treated patients than in the placebo control group

Palifermin After Haploidentical PBSCT

Randomised Placebo-Controlled Double-Blind Phase II Study Applying Palifermin to Improve T-cell Immune Reconstitution After Haploidentical Allogeneic Peripheral Blood Progenitor Cell (PBPC) Transplantation

Amgen

European Society for Blood and Marrow Transplantation

Kim Champion

Heart and Blood Diseases

Polycythemia Vera

Polycythemia

Primary Myelofibrosis

Thrombocytosis

Thrombocythemia, Essential

Metaplasia

Bone Marrow Neoplasms

Hematologic Neoplasms

Blood Platelet Disorders

Hemostatic Disorders

Blood Coagulation Disorders

Hemorrhagic Disorders

Essential Thrombocythemia

Antineoplastic Agents

Decitabine

Spartalizumab

Antimetabolites

Enzyme Inhibitors

Immune Checkpoint Inhibitors

Antineoplastic Agents, Immunological

Treatment with NIS793 + MBG453 + Spartalizumab

treatment with NIS793 + MBG453 + Decitabine

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).

MBG453

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).

NIS793

Intravenous. 300mg. Every first day of a 21-day cycle

Intravenous. Starting dose: 5mg/m2 (dose cap at 20mg/m2). On days 1, 2 and 3 of a 42-day cycle

Alesandro Pastore Novartis Pharmaceuticals

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)

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.

Study of Select Combinations in Adults With Myelofibrosis

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

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).

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.

Tolerability measured by the number of subjects who have interruptions of study treatment and reason for interruptions

Tolerability measured by the number of subjects who have reductions of study treatment and reason for reductions

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

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.

Proportion of subjects achieving improvement of Hb level of ≥ 1.5 g/dL from baseline

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%.

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.

The maximum observed plasma, blood serum or other body fluid drug concentration

Time to reach maximum plasma, blood serum or other body fluid drug concentration

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Palifermin After Haploidentical PBSCT	NCT00570999	Non-Hodgkin's L... Acute Leukaemia Myelodysplastic... Chronic Myeloid... Osteomyelofibro...	Palifermin Placebo	18 Years - 65 Years	European Society for Blood and Marrow Transplantation
Palifermin After Haploidentical PBSCT	NCT00570999	Non-Hodgkin's L... Acute Leukaemia Myelodysplastic... Chronic Myeloid... Osteomyelofibro...	Palifermin Placebo	18 Years - 65 Years	European Society for Blood and Marrow Transplantation
Study of Select Combinations in Adults With Myelofibrosis	NCT04283526	Primary Myelofi... Myelofibrosis PMF Post-Essential ... Post-Polycythem...	MBG453 NIS793 Spartalizumab Decitabine	18 Years -	Novartis

Spots Global Cancer Trial Database for osteomyelofibrosis