Study of Select Combinations in Adults With Myelofibrosis

NCT ID: NCT04283526

Last Updated: 2021-03-04

Basic Information

• Recruitment Status: WITHDRAWN
• Clinical Phase: PHASE1
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-11-30
• Study Completion Date: 2024-04-11

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.

Conditions

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

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

NIS793 + MBG453

treatment with NIS793 + MBG453

Group Type: EXPERIMENTAL

MBG453

Intervention Type: 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).

NIS793

Intervention Type: 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 + MBG453 + Spartalizumab

Treatment with NIS793 + MBG453 + Spartalizumab

Group Type: EXPERIMENTAL

MBG453

Intervention Type: 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).

NIS793

Intervention Type: 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).

Spartalizumab

Intervention Type: DRUG

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

NIS793 + MBG453 + Decitabine

treatment with NIS793 + MBG453 + Decitabine

Group Type: EXPERIMENTAL

MBG453

Intervention Type: 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).

NIS793

Intervention Type: 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).

Decitabine

Intervention Type: DRUG

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

NIS793

treatment with NIS793

Group Type: EXPERIMENTAL

NIS793

Intervention Type: 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).

MBG453

treatment with MBG453

Group Type: EXPERIMENTAL

MBG453

Intervention Type: 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).

Interventions

MBG453

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).

Intervention Type: DRUG

NIS793

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).

Intervention Type: DRUG

Spartalizumab

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

Intervention Type: DRUG

Decitabine

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

Intervention Type: DRUG

Other Intervention Names

PDR001; Dacogen

Eligibility Criteria

Inclusion Criteria

1. Signed informed consent must be obtained prior to participation in the study.

2. Male or female subjects must be ≥ 18 years of age at the time of signing the informed consent form (ICF).

3. 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).

4. 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.

5. 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).

6. Absolute neutrophil count (ANC) ≥ 1000/μL.

7. Dose evaluation / Dose escalataion: Platelet count ≥ 75,000/μL without transfusion support Dose expansion: Platelet count ≥ 50,000/μL without transfusion support.

Exclusion Criteria

1. Subjects with Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), or peripheral blasts ≥ 10 %, or AML transfromed from previous MPN.

2. 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.

3. Prior autologous or allogeneic stem cell transplant at any time.

4. Candidate for allogenic hematopoietic stem cell transplantation at the time of enrolment.

5. Splenic irradiation within 6 months prior to the first dose of study treatment.

6. Prior splenectomy.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Alesandro Pastore Novartis Pharmaceuticals

Role: STUDY_DIRECTOR

Novartis Pharmaceuticals

Other Identifiers

2019-003738-18

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CMBG453D12101

Identifier Type: -

Identifier Source: org_study_id