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Primary MyelofibrosisPhase 1NCT04283526

Study of Select Combinations in Adults With Myelofibrosis

A Phase 1 study testing MBG453, NIS793 and Spartalizumab in people with Primary Myelofibrosis and Myelofibrosis, run by Novartis Pharmaceuticals.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Primary Myelofibrosis, Myelofibrosis, PMF
What is being tested?
MBG453, NIS793 and Spartalizumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
30 Nov 2020to 11 Apr 2024
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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:
Show all 11Show fewer
  • 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.

Who cannot join

  • 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.

About this study

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

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)

Read the 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.

Being tested
MBG453, NIS793, Spartalizumab, Decitabine
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)
Medical subject headings
Primary Myelofibrosis, Myeloproliferative Disorders, Polycythemia Vera, Thrombocythemia, Essential

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • MBG453Drug

    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).

  • NIS793Drug

    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).

  • SpartalizumabDrug

    Also called PDR001

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

  • DecitabineDrug

    Also called Dacogen

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

Study groups in NCT04283526
Study groupRoleWhat they receive
NIS793 + MBG453Experimentaltreatment with NIS793 + MBG453
Receives: Drug: MBG453; Drug: NIS793
NIS793 + MBG453 + SpartalizumabExperimentalTreatment with NIS793 + MBG453 + Spartalizumab
Receives: Drug: MBG453; Drug: NIS793; Drug: Spartalizumab
NIS793 + MBG453 + DecitabineExperimentaltreatment with NIS793 + MBG453 + Decitabine
Receives: Drug: MBG453; Drug: NIS793; Drug: Decitabine
NIS793Experimentaltreatment with NIS793
Receives: Drug: NIS793
MBG453Experimentaltreatment with MBG453
Receives: Drug: MBG453

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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).

    Measured: 12 months

  2. 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.

    Measured: 36 months

  3. Dose interruptions

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

    Measured: 36 months

  4. Dose reductions

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

    Measured: 36 months

  5. 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

    Measured: 36 montths

Secondary outcomes (6)

  1. 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.

    Measured: 36 months

  2. Proportion of subjects achieving improvement of Anemia

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

    Measured: 36 months

  3. 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%.

    Measured: 36 months

  4. 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.

    Measured: 36 months

  5. Cmax (Maximum Concentration)

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

    Measured: 36 months

  6. Tmax

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

    Measured: 36 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted25 Feb 2020
  2. Study start30 Nov 2020 (estimated)
  3. Primary completion11 Apr 2024 (estimated)
  4. Study completion11 Apr 2024 (estimated)

Why it stopped: This study was cancelled before enrolling any patients for business related reasons.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Crossover
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04283526
Sponsor's protocol ID
CMBG453D12101
Other IDs
2019-003738-18, 2019
Status last verified
Mar 2021
First submitted
21 Feb 2020
Last updated
4 Mar 2021
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing MBG453, NIS793 and Spartalizumab in people with Primary Myelofibrosis and Myelofibrosis, run by Novartis Pharmaceuticals.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 4 Mar 2021. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of Dose limiting toxicities (DLT) (time frame: 12 months). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04283526.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Mar 2021.

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