To characterize the safety, tolerability, and recommended phase 2 dose (RP2D) of each combination partner used with ruxolitinib (Part 1)To evaluate the preliminary efficacy of each novel ruxolitinib combination treatment arm (Parts 2 & 3)
ID
Source
Brief title
Condition
- Haematological disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The efficacy assessments for the primary objectives are:
**Laboratory hemoglobin assessments taken at the end of Cycle 6 compared to
baseline
**MRI or CT imaging of the spleen will be performed at screening, at the end of
Cycle 6, the end of Cycle 12 and at end of treatment (EOT)
**total symptom score (TSS) assessed by MFSAF v4.0 at baseline and at the end
of Cycle 6
Secondary outcome
To assess the proportion of subjects in each treatment arm who achieve an Hb
improvement of * 2.0 g/dL or * 1.5 g/dL from baseline to the end of
Cycle 6 and end of Cycle 12
To evaluate the changes in spleen size in each treatment arm measured by change
in spleen length (by palpation) and spleen volume (by
magnetic resonance imaging (MRI)/computed topography (CT)) from baseline
To evaluate changes in symptoms of myelofibrosis in each treatment arm using
MFSAF v4.0 and European Organization for Research and
Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30)
patient reported outcomes (PROs) from baseline
To characterize the pharmacokinetic profile of ruxolitinib administered in
combination with siremadlin, crizanlizumab, sabatolimab, LTT462 and NIS793.
Background summary
MF is defined by progressive bone marrow fibrosis, Anemia is among the cardinal
features of MF. Nearly 40% of MF patients have hemoglobin (Hb) levels < 10 g/dL
at diagnosis, and nearly one-quarter are already red blood cell (RBC)
transfusiondependent. All patients with MF will eventually develop anemia,
which has consistently been associated with inferior QoL measures. Furthermore,
anemia is the disease feature most consistently associated with poor prognosis
in MF.
Ruxolitinib demonstrated improvements in splenomegaly and constitutional
symptoms. However, not all patients respond to ruxolitinib, with some losing
response while on treatment, and some having to discontinue treatment owing to
toxicities. Ruxolitinib does not improve cytopenias but may aggravate anemia
due to transient suppression of the erythropoiesis, which at least partially
resolves over time on continuous therapy. Current treatment options for these
patients are limited in their efficacy, durability and tolerability. Anemia and
thrombocytopenia have remained challenges in the management of MF and represent
a high unmet medical need. Combination therapies of ruxolitinib with novel
agents may deliver transformational clinical benefits such as improvement of
PFS, associated with an improvement of cytopenia and in particular anemia, as
well as improvement in QoL.
The purpose of this study is to investigate the safety, pharmacokinetics and
preliminary efficacy of combinations treatment of ruxolitinib with five novel
compounds: siremadlin, crizanlizumab, sabatolimab, LTT462 and NIS793 in MF
subjects.
Study objective
To characterize the safety, tolerability, and recommended phase 2 dose (RP2D)
of each combination partner used with ruxolitinib (Part 1)
To evaluate the preliminary efficacy of each novel ruxolitinib combination
treatment arm (Parts 2 & 3)
Study design
This is an open-label, multi-center, three-part, phase Ib/II open platform
study to assess safety and efficacy of ruxolitinib in combination with novel
compounds in myelofibrosis patients. The study consists of three parts:
**Part 1: Dose escalation and safety-run-in (recommended Phase II dose
confirmation)
**Part 2: Selection
**Part 3: Expansion
Intervention
In Part 1 of the study, subjects will be allocated during screening to one of
the following 5 treatment arms:
- Arm 1: Ruxolitinib 5-25 mg PO BID and siremadlin at various dose levels
(either 10 mg, 20 mg (starting dose), 30 mg or 40 mg) PO on Days 1 to 5 of a
28-day cycle
- Arm 2: Ruxolitinib 5-25 mg PO BID and crizanlizumab 5 mg/kg IV Q4W
- Arm 3: Ruxolitinib 5-25 mg PO BID and MBG453 800 mg IV Q4
- Arm 4: Ruxolitinib 5-25 mg PO BID and LTT462 100-300mg PO QD (in a 28 day
cycle)
- Arm 5: Ruxolitinib 5-25 mg PO BID and NIS793 2100 mg IV Q3W
In Part 2 of the study, subjects will be randomized during screening to one of
the following 6 treatment arms in a ratio of 1:1:1:1:1:1 with approximately 25
subjects per arm:
- Arm 1: ruxolitinib 5-25 mg PO BID and siremadlin at the RP2D from Part 1 PO
on Days 1 to 5 of a 28-day cycle
- Arm 2: ruxolitinib 5-25 mg PO BID and crizanlizumab 5 mg/kg IV Q4W
- Arm 3: ruxolitinib 5-25 mg PO BID and MBG453 800 mg IV Q4W
- Arm 4: Ruxolitinib 5-25 mg PO BID and LTT462 (R2PD) PO QD (in a 28 day cycle)
- Arm 5: Ruxolitinib 5-25 mg PO BID and NIS793 2100 mg IV Q3W
- Arm 6: ruxolitinib 5-25 mg PO BID monotherapy control
In Part 3 of the study, subjects will be randomized during screening to one of
the following 3 treatment arms in a ratio of 2:1:1 with approximately 20, 10,
and 10 subjects per arm, respectively:
**Arm 1: Ruxolitinib 5-25 mg PO BID and novel compound from Part 2 (TBD)
**Arm 2: Ruxolitinib 5-25 mg PO BID and novel compound from Part 2 (TBD) for 3
cycles of treatment, followed by ruxolitinib cessation treatment (i.e. novel
agent monotherapy control)
**Arm 3: Ruxolitinib 5-25 mg PO BID monotherapy control
Study burden and risks
Intensive PK sampling for all patients, infusions on day 1 of each cycle
(compaed to standard treatment with ruxolitinib) for 2/3 of patients. Other 1/3
of patients will be randomised to siremadlin (oral capsules)
Risks: side effects of the medications (combinations) and of the test
procedures like extra blooddraws.
Haaksbergweg 16
Amsterdam 1101 BX
NL
Haaksbergweg 16
Amsterdam 1101 BX
NL
Listed location countries
Age
Inclusion criteria
* Subjects have diagnosis of primary myelofibrosis (PMF) according to the 2016
World Health Organization (WHO) criteria, or diagnosis of post-essential
thrombocythemia (ET) (PET-MF) or post-polycythemia vera (PV) myelofibrosis
(PPV-MF) according to the International Working Group for Myelofibrosis
Research and Treatment (IWG-MRT) 2007 criteria
* Palpable spleen of at least 5 cm or enlarged spleen volume of at least 450
cm3 per MRI or CT scan at baseline (a MRI/CT scan up to 8 weeks prior to first
dose of study treatment can be accepted).
* Have been treated with ruxolitinib for at least 12 weeks prior to first dose
of study treatment
* Are stable (no dose adjustments) on the prescribed ruxolitinib dose (between
5 and 25 mg twice a day (BID)) for * 4 weeks prior to first dose of study
treatment.
* Hemoglobin < 11 g/dL
* Part 1: Platelet counts * 75 000/*L
* Part 2 and Part 3: Platelet counts * 50 000/*L
Exclusion criteria
* Not able to understand and to comply with study instructions and
requirements.
* Received any investigational agent for the treatment of MF (except
ruxolitinib) within 30 days of first dose of study treatment or within 5
half-lives of the study treatment, whichever is greater
* Peripheral blood blasts count of >10%.
* Received a monoclonal antibody (Ab) or immunoglobulin-based agent within 1
year of screening, or has documented severe hypersensitivity
reactions/immunogenicity (IG) to a prior biologic
* Splenic irradiation within 6 months prior to the first dose of study drug
* Received blood platelet transfusion within 28 days prior to first dose of
study treatment. PRBC transfusions are permitted
* Subjects with known TP53 mutation or deletion of TP53
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-000373-23-NL |
| CCMO | NL70284.056.19 |