Neoplasms

Blood and Lymph Conditions

All Conditions

Heart and Blood Diseases

Rare Diseases

Polycythemia Vera

Polycythemia

Primary Myelofibrosis

Thrombocytosis

Thrombocythemia, Essential

Myeloproliferative Disorders

Bone Marrow Diseases

Hematologic Diseases

Bone Marrow Neoplasms

Hematologic Neoplasms

Blood Platelet Disorders

Hemostatic Disorders

Blood Coagulation Disorders

Hemorrhagic Disorders

Essential Thrombocythemia

Chronic Myeloproliferative Disorders

Natriuretic Agents

All Drugs and Chemicals

Mannitol

Patients will receive PXS-5505 dose level 1, twice daily for a period of 4 weeks.

Patients will receive PXS-5505 dose level 2, twice daily for a period of 4 weeks.

Patients will receive PXS-5505 dose level 3, twice daily for a period of 4 weeks.

All patients will receive PXS-5505 at the selected twice daily dose for a period of 24 weeks, or until progressive disease, unacceptable toxicity, dose-limiting toxicity or withdrawal of consent.

Patients already receiving a stable dose of ruxolitinib for at least 12 weeks, will receive PXS-5505 (the dose used in the cohort expansion phase) on top of their ruxolitinib dose for up to 52 weeks or until progressive disease, unacceptable toxicity, dose-limiting toxicity, or withdrawal of consent.

PXS-5505 is a hard capsule (size 0) with the additional excipients mannitol and magnesium stearate.

PXS-5505

Jana Baskar, MBBS MMedSc MBA

Vachhani Pankit

Chen Franklin

Masarova Lucia

Pinky Patel

Stanley Cheung

Tan Shuhying

Peter Tan

Shona Garlick

Won Sik Lee

Do 도 Young Rok 영록

Sung-Eun Lee

Chih-Cheng 志丞 Chen 陳

Hui-Hua 惠樺 Hsiao 蕭

Su-Peng 士芃 Yeh 葉

Chen 陳 Tsai-Yun 彩雲

Shang-Ju 尚儒 Wu 吳

This study will be an open-label phase 1/2a study to evaluate the safety and tolerability of PXS-5505 in patients with primary, postpolycythemia vera (PV) or post-essential thrombocythemia (ET) myelofibrosis.

The study consists of three phases: a dose escalation phase, a cohort expansion phase, and an add-on phase.

The dose escalation phase will follow a 3+3 design with a starting dose of 100 mg twice daily, and a treatment duration of 4 weeks. Patients will be able to participate in more than one dose level.

During the cohort expansion phase, up to 24 patients will be treated at the dose determined appropriate based on safety, pharmacokinetic and pharmacodynamic results from the dose escalation phase, for a period of up to 6 months. Patients from the dose escalation phase will be able to participate in the cohort expansion phase.

In the add-on phase PXS-5505 will be given to patients, already receiving a stable dose of ruxolitinib, for a period of 12 months. Up to 15 patients will enrol in the add-on phase in order to obtain 12 patients with at least 1 month's exposure to PXS-5505 on top of ruxolitinib.

Note: The decision to include an add-on phase, where PXS-5505 is to be given on top of a stable ruxolitinib dose, was taken following a review of the data (safety, PK and PD) from the cohort expansion phase.

There will be no washout period between dose escalation and dose expansion cohorts.

Study to Evaluate Safety, Pharmacokinetic and Pharmacodynamic Dose Escalation and Expansion Study of PXS-5505 in Patients With Primary, Post-polycythemia Vera or Post-essential Thrombocythemia Myelofibrosis

A Phase 1/2a Study to Evaluate Safety, Pharmacokinetic and Pharmacodynamic Dose Escalation and Expansion Study of PXS-5505 in Patients With Primary, Postpolycythemia Vera or Post-essential Thrombocythemia Myelofibrosis

Safety and tolerability of PXS-5505 in patients with myelofibrosis will be assessed

Pharmacokinetic parameters of PXS-5505 in patients with myelofibrosis will be assessed.

Pharmacodynamic parameters of PXS-5505 in patients with myelofibrosis will be assessed.

Change in bone marrow fibrosis will be assessed according to European Consensus on grading of bone marrow fibrosis

Response rates as defined by International Working Group (IWG)-Myeloproliferative Neoplasms Research and Treatment criteria in patients with myelofibrosis administered PXS-5505 will be determined.

Changes in spleen volume, as measured by computed tomography (CT) or magnetic resonance imaging (MRI) scan, in patients with myelofibrosis administered PXS-5505 will be determined.

Changes in myelofibrosis related symptoms based on Myelofibrosis-Symptom Assessment Form (MFSAF) v4.0 scores, in patients with myelofibrosis administered PXS-5505 will be determined. A higher score indicates worse symptoms.

Syntara

Leukemia

Participants in Stage 1 of study will receive simtuzumab 200 mg for up to 24 weeks. Treatment could be continued if there is evidence of clinical benefit as judged by the treating physician.

Participants in Stage 1 of study will receive simtuzumab 700 mg for up to 24 weeks. Treatment could be continued if there is evidence of clinical benefit as judged by the treating physician.

In Stage 2, participants on stable doses of ruxolitinib will receive simtuzumab 200 mg for at least 24 weeks. Treatment could be continued if there is evidence of clinical benefit as judged by the treating physician.

In Stage 2, participants on stable doses of ruxolitinib will receive simtuzumab 700 mg for at least 24 weeks. Treatment could be continued if there is evidence of clinical benefit as judged by the treating physician.

Simtuzumab administered intravenously over approximately 30 minutes every 2 weeks

Simtuzumab

In Stage 2, participants will be on a stable dose of ruxolitinib

Ruxolitinib

Gilead Study Director

This study is to evaluate the efficacy and safety of simtuzumab (GS-6624) on bone marrow fibrosis either alone or in combination with ruxolitinib in participants with primary myelofibrosis (PMF) and post polycythemia vera or post essential thrombocythemia myelofibrosis (ET/PV MF).

The study is designed as a two-stage trial. In the stage 1, participants will be randomized into two cohorts to receive either 200 or 700 mg of study drug. In the stage 2, participants on ruxolitinib will be randomized to receive either 200 or 700 mg of study drug.

Efficacy and Safety of Simtuzumab in Adults With Primary, Post Polycythemia Vera or Post Essential Thrombocythemia Myelofibrosis

A Phase 2 Study to Evaluate the Efficacy and Safety of GS-6624 in Adult Subjects With Primary, Post Polycythemia Vera or Post Essential Thrombocythemia Myelofibrosis

Overall response for the study drug is defined by the reduction in bone marrow fibrosis score which is on a scale of 0-3 where 0 indicates the scattered linear reticulin with no fiber intersections representing normal marrow and 3 indicates dense increase in reticulin fibrosis with fiber intersections, often with osteosclerosis. Reduction from baseline of score indicates improvement in clinical condition.

Overall response for the study drug was defined by the rate of clinical improvement in hemoglobin, platelet or ANC. Clinical improvement in hemoglobin was defined as a ≥ 2 g/dL increase from baseline in hemoglobin level and transfusion independent (absence of red blood cell (RBC) transfusions in prior 8 weeks and applicable only for participants with baseline hemoglobin level of \< 10 g/dL); clinical improvement in platelets was defined as a ≥ 100% increase from baseline in platelet count and an absolute platelet count of ≥ 50 x 10\^9/L (applicable only for participants with baseline platelet count \< 50 x 10\^9/L); clinical improvement in ANC is defined as a ≥ 100% increase from baseline in ANC and an ANC of ≥ 0.5 x 10\^9/L (applicable only for participants with baseline ANC \< 1 x 10\^9/L).

Myelofibrosis symptom assessment was performed using myeloproliferative neoplasm symptoms assessment form (MPN-SAF) which is a 27-item questionnaire to address symptom burden and quality of life. The form consists of 27 questions which are scored on a scale of 0-10 by participants based on how symptoms are affecting them, where 0 indicates less symptoms while 10 indicated more severe symptoms and greater inactivity. The MPN-SAF score was calculated at each visit for each participant as an average of the scales for each question and all answered questions. If the number of questions not answered at 1 visit was \> 10, then the MPN-SAF score for that visit was taken as missing. A negative change from Baseline indicated improvement.

Biomarker samples were collected to evaluate the effects of SIM treatment on markers of serum and plasma cytokines.

Blood samples were collected for the presence of anti-SIM antibodies which was determined using a validated electro-chemiluminescent (ECL) assay screening test.

Gilead Sciences

The Safety Analysis Set included participants who were randomized and received at least 1 dose of study drug.

Participants were administered simtuzumab (SIM) 200 mg intravenous (IV) infusion over 30 minutes once every 2 weeks for a total of 6 infusions per 12-week cycle for up to 94 weeks.

Stage 1: SIM 200 mg

Participants were administered SIM 700 mg IV infusion over 30 minutes once every 2 weeks for a total of 6 infusions per 12-week cycle for up to 40 weeks.

Stage 1: SIM 700 mg

Participants on a stable dose of ruxolitinib were administered SIM 200 mg IV infusion over 30 minutes once every 2 weeks for up to 91 weeks.

Stage 2: SIM 200 mg+Ruxolitinib

Participants on a stable dose of ruxolitinib were administered SIM 700 mg IV infusion over 30 minutes once every 2 weeks for up to 86 weeks.

Stage 2: SIM 700 mg+Ruxolitinib

Total

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race

Race/Ethnicity, Customized

The Per Protocol Analysis Set included participants who were randomized, received at least 1 dose of study drug, did not violate any major entry criteria and had at least 80% adherence with study drug. It is measured on a scale of 0-3 where 0 indicates normal marrow and 3 indicates fibrosis. For additional description, please see outcome measure 1.

Bone Marrow Fibrosis Score

Gilead Clinical Study Information Center

The Per Protocol Analysis Set included participants who were randomized, received at least 1 dose of study drug, did not violate any major entry criteria, and had at least 80% adherence with study drug.

Rate of Clinical Response as Defined by the Percentage of Participants With Reduction at Week 24 From Baseline in the Bone Marrow Fibrosis Score

Week 12

Week 24

Any Time Post-Baseline

Participants were administered SIM 200 mg IV infusion over 30 minutes once every 2 weeks for a total of 6 infusions per 12-week cycle for up to 94 weeks.

Participants in Per Protocol Analysis Set with available data were analyzed.

Rate of Clinical Response as Defined by the Percentage of Participants With Improvement in Hemoglobin, Platelet, or Absolute Neutrophil Count (ANC)

The Safety Analysis Set included participants who were randomized and received at least 1 dose of study drug

Percentage of Participants With Adverse Events (AEs)

Baseline

Best Change from Baseline

Change from Baseline at Cycle 1 - Day 43

Change from Baseline at Cycle 1 - Day 85

Change from Baseline at Cycle 2 - Day 43

Change from Baseline at Cycle 2 - Day 85

Change from Baseline at Cycle 3 - Day 43

Change from Baseline at Cycle 3 - Day 85

Change from Baseline at Cycle 4 - Day 43

Change from Baseline at Cycle 4 - Day 85

Change from Baseline at Cycle 5 - Day 43

Change from Baseline at Cycle 5 - Day 85

Change from Baseline at Cycle 6 - Day 43

Change from Baseline at Cycle 6 - Day 85

Change from Baseline at Cycle 7 - Day 43

Change from Baseline at Cycle 7 - Day 85

Participants in the Per Protocol Analysis Set with available data were analyzed.

Change From Baseline in Myelofibrosis Symptoms Assessment Score

Change From Baseline in Cytokine Levels

Baseline : Screened Negative

Baseline : Screened Positive

Cycle 1 - Day 85 : Screened Negative

Cycle 1 - Day 85 : Screened Positive

Cycle 2 - Day 85 : Screened Negative

Cycle 2 - Day 85 : Screened Positive

Cycle 3 - Day 85 : Screened Negative

Cycle 3 - Day 85 : Screened Positive

Cycle 4 - Day 85 : Screened Negative

Cycle 4 - Day 85 : Screened Positive

Cycle 5 - Day 85 : Screened Negative

Cycle 5 - Day 85 : Screened Positive

Participants in Safety Analysis Set with available data were analyzed.

Percentage of Participants With Anti-Simtuzumab Antibody Formation

Overall Study

Symptoms and General Pathology

Metaplasia

Chronic Graft Versus Host Disease

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
Study to Evaluate Safety, Pharmacokinetic and Pharmacodynamic Dose Escalation and Expansion Study of PXS-5505 in Patients With Primary, Post-polycythemia Vera or Post-essential Thrombocythemia Myelofibrosis	NCT04676529	Myelofibrosis	PXS-5505	18 Years -	Syntara
Study to Evaluate Safety, Pharmacokinetic and Pharmacodynamic Dose Escalation and Expansion Study of PXS-5505 in Patients With Primary, Post-polycythemia Vera or Post-essential Thrombocythemia Myelofibrosis	NCT04676529	Myelofibrosis	PXS-5505	18 Years -	Syntara
Study to Evaluate Safety, Pharmacokinetic and Pharmacodynamic Dose Escalation and Expansion Study of PXS-5505 in Patients With Primary, Post-polycythemia Vera or Post-essential Thrombocythemia Myelofibrosis	NCT04676529	Myelofibrosis	PXS-5505	18 Years -	Syntara
Efficacy and Safety of Simtuzumab in Adults With Primary, Post Polycythemia Vera or Post Essential Thrombocythemia Myelofibrosis	NCT01369498	Myelofibrosis	Simtuzumab Ruxolitinib	18 Years -	Gilead Sciences
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 thrombocythemia myelofibrosis