Study of Select Combinations in Adults With Myelofibrosis

NCT04283526 | Withdrawn Phase 1 FDA Drug

• 2 other identifiers: CMBG453D121012019-003738-18
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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)

Conditions

Primary Myelofibrosis; Myelofibrosis; PMF; Post-Essential Thrombocythemia Myelofibrosis; Post-Polycythemia Vera Myelofibrosis

Keywords

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)

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (6)

• 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

  36 months

• Proportion of subjects achieving improvement of Anemia

  36 months

• Progression-free survial time (PFS)

  36 months

• Duration of response

  36 months

• Cmax (Maximum Concentration)

  36 months

Study Arms (5)

NIS793 + MBG453

EXPERIMENTAL

treatment with NIS793 + MBG453

Drug: MBG453; Drug: NIS793

NIS793 + MBG453 + Spartalizumab

EXPERIMENTAL

Treatment with NIS793 + MBG453 + Spartalizumab

Drug: MBG453; Drug: NIS793; Drug: Spartalizumab

NIS793 + MBG453 + Decitabine

EXPERIMENTAL

treatment with NIS793 + MBG453 + Decitabine

Drug: MBG453; Drug: NIS793; Drug: Decitabine

NIS793

EXPERIMENTAL

treatment with NIS793

Drug: NIS793

MBG453

EXPERIMENTAL

treatment with MBG453

Drug: MBG453

Interventions

MBG453 DRUG

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; NIS793 + MBG453; NIS793 + MBG453 + Decitabine; NIS793 + MBG453 + Spartalizumab

NIS793 DRUG

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; NIS793 + MBG453; NIS793 + MBG453 + Decitabine; NIS793 + MBG453 + Spartalizumab

Spartalizumab DRUG

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

Also known as: PDR001

NIS793 + MBG453 + Spartalizumab

Decitabine DRUG

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

Also known as: Dacogen

NIS793 + MBG453 + Decitabine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

MeSH Terms

Conditions

Primary Myelofibrosis; Myeloproliferative Disorders; Polycythemia Vera; Thrombocythemia, Essential

Interventions

sabatolimab; NIS-793; spartalizumab; Decitabine

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Neoplasms; Hematologic Neoplasms; Neoplasms by Site; Neoplasms; Blood Coagulation Disorders; Thrombocytosis; Blood Platelet Disorders; Hemorrhagic Disorders

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Alesandro Pastore Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 21, 2020
• First Posted: February 25, 2020
• Study Start: November 30, 2020
• Primary Completion: April 11, 2024
• Study Completion: April 11, 2024
• Last Updated: March 4, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share