The purpose of this study is to investigate the safety, pharmacokinetics and preliminary efficacy of combinations treatment of ruxolitinib with 5 novel compounds: siremadlin, crizanlizumab, sabatolimab, LTT462 and NIS793 in myelofibrosis (MF) subjects.
Recruiting
Phase 1/Phase 2
| Drug | Synonyms | Arms |
|---|---|---|
| Ruxolitinib | INC424, Jakavi | Part 1 Arm 1: Ruxolitinib + Siremadlin |
| Siremadlin | HDM201 | Part 1 Arm 1: Ruxolitinib + Siremadlin |
| Crizanlizumab | SEG101 | Part 1 Arm 2: Ruxolitinib + Crizanlizumab |
| Sabatolimab | MBG453 | Part 1 Arm 3: Ruxolitinib + Sabatolimab |
| LTT462 | Part 1 Arm 4: Ruxolitinib + LTT462 | |
| NIS793 | Part 1 Arm 5: Ruxolitinib + NIS793 |
| Name | Type | Description | Interventions |
|---|---|---|---|
| Part 1 Arm 1: Ruxolitinib + Siremadlin | Experimental | Dose escalation of siremadlin added to existing stable dose of ruxolitinib |
|
| Part 1 Arm 2: Ruxolitinib + Crizanlizumab | Experimental | Safety run-in of crizanlizumab added to existing stable dose of ruxolitinib |
|
| Part 1 Arm 3: Ruxolitinib + Sabatolimab | Experimental | Safety run-in of Sabatolimab added to existing stable dose of ruxolitinib |
|
| Part 2 Arm 1: Ruxolitinib + Siremadlin | Experimental | Siremadlin added to existing stable dose of ruxolitinib |
|
| Part 2 Arm 2: Ruxolitinib + Crizanlizumab | Experimental | Crizanlizumab added to existing stable dose of ruxolitinib |
|
| Part 2 Arm 3: Ruxolitinib + Sabatolimab | Experimental | Sabatolimab added to existing stable dose of ruxolitinib |
|
| Part 2 Arm 6: Ruxolitinib monotherapy | Active Comparator | Existing stable dose of ruxolitinib as control for Part 2 |
|
| Part 3 Arm 1: Ruxolitinib + Compound X | Experimental | Compound from Part 2 (to be confirmed) added to existing stable dose of ruxolitinib |
|
| Part 3 Arm 2: Ruxolitinib cessation | Experimental | Compound from Part 2 added to existing stable dose of ruxolitinib for 3 cycles followed by compound monotherapy |
|
| Part 3 Arm 3: Ruxolitinib monotherapy | Active Comparator | Existing stable dose of ruxolitinib as control for Part 3 |
|
| Part 1 Arm 4: Ruxolitinib + LTT462 | Experimental | Dose escalation of LTT462 added to existing stable dose of ruxolitinib |
|
| Part 1 Arm 5: Ruxolitinib + NIS793 | Experimental | Safety run-in of NIS793 added to existing stable dose of ruxolitinib |
|
| Part 2 Arm 4: Ruxolitinib + LTT462 | Experimental | LTT462 added to existing stable dose of ruxolitinib |
|
| Part 2 Arm 5: Ruxolitinib + NIS793 | Experimental | NIS793 added to existing stable dose of ruxolitinib |
|
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 from the left costal margin (LCM) to the point of
greatest splenic protrusion 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 24 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 ≥ 8 weeks prior to first dose of study treatment
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.
Other protocol-defined Inclusion/Exclusion criteria may apply.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Incidence of dose limiting toxicities within the first 2 cycles |
| Time Frame: | Baseline to the end of Cycle 2 (6 or 8 weeks) |
| Safety Issue: | |
| Description: | Incidence and severity of dose limiting toxicities within the first 2 cycles (6 or 8 weeks) in Part 1 of the study |
| Measure: | Proportion of subjects achieving an improvement in hemoglobin level of ≥ 1.5 g/dL from baseline |
| Time Frame: | Baseline to the end of Cycle 6 or 8 (24 weeks), and end of Cycle 12 or 16 (48 weeks) |
| Safety Issue: | |
| Description: | Proportion of subjects achieving an improvement in hemoglobin level of at least >= 1.5 g/dL from baseline at each time point in Part 2 and Part 3 of the study. |
| Measure: | Proportion of subjects achieving an improvement in hemoglobin level of at least >= 2.0 g/dL from baseline |
| Time Frame: | Baseline to the end of Cycle 6 or 8 (24 weeks), and end of Cycle 12 or 16 (48 weeks) |
| Safety Issue: | |
| Description: | Proportion of subjects achieving an improvement in hemoglobin level of at least >= 2.0 g/dL from baseline at each time point in Part 2 and Part 3 of the study. |
| Measure: | Change in spleen length from baseline |
| Time Frame: | Baseline to day 1 and day 15 of Cycle 1, 2 and 3, day 1 of all subsequent cycles, and the end of 12 or 16 cycles (48 weeks) |
| Safety Issue: | |
| Description: | Change in spleen length measured in centimeters by manual palpation summarized at each time point using descriptive statistics in Part 2 and Part 3 of the study |
| Measure: | Change in spleen volume from baseline |
| Time Frame: | Baseline to the end of Cycle 6 or 8 (24 weeks), the end of Cycle 12 or 16 (48 weeks) and at the end of treatment if not performed in the past 12 weeks (up to 48 weeks) |
| Safety Issue: | |
| Description: | Change in spleen volume measured by magnetic resonance imaging (MRI) or computed tomography (CT) summarized at each time point using descriptive statistics, in Part 2 and Part 3 of the study |
| Measure: | Change in symptoms of MFSAF v4.0 from baseline |
| Time Frame: | Baseline to day 1 of Cycle 1, day 1 of all subsequent cycles of treatment (each cycle is 28 days except for arms containing NIS793, which are 21 days), as well as the end of treatment visit (approximately 52 weeks) |
| Safety Issue: | |
| Description: | Change in total symptom scores (TSS) assessed by the Myelofibrosis (MF Symptom Assessment Form version 4.0 (MFSAF v4.0) at each time point in Part 2 and Part 3 of the study. The MFSAF v4.0 questionnaire focuses on the 7 core symptoms of MF: fatigue, night sweats, pruritus, abdominal discomfort, pain under the ribs on the left side, early satiety and bone pain. Subjects record symptom severity at it worst for each of the 7 symptoms on an 11-point numeric rating scale, from 0 (absent) to 10 (worst imaginable). The Total Symptom Score (TSS) is the sum of all the scores for all 7 symptoms. |
| Measure: | Change in symptoms of EORTC QLQ-C30 from baseline |
| Time Frame: | Baseline to day 1 of Cycle 1, day 1 of all subsequent cycles of treatment (each cycle is 28 days except for arms containing NIS793, which are 21 days), as well as the end of treatment visit (approximately 52 weeks) |
| Safety Issue: | |
| Description: | Change in symptom scores assessed by European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire (EORTC QLQ C-30) at each time point in Part 2 and Part 3 of the study. The EORTC QLQ-C30 includes 5 functional scales (physical, emotional, social, role, cognitive), eight symptom scales (fatigue, pain, nausea/vomiting, constipation, diarrhea, insomnia, dyspnea, and appetite loss), as well as global health/quality-of-life and financial impact. Subjects respond according to the past week recall period, with the exception of the first 5 questions that represent physical functioning and capture the subject's current status. Raw scores are linearly converted to a 0-100 scale. For functional and global health status/QoL higher scores indicate better QoL and level of functioning; for symptom scales, higher scores indicate greater level of symptoms or difficulties. |
| Measure: | Progression free survival, per progressive splenomegaly, accelerated phase, deteriorating cytopenia, leukemic transformation or death from any cause |
| Time Frame: | Baseline to disease progression, which is up to 24 weeks for Part 1 or through study completion, an average of 1 year, for Part 2 and Part 3 |
| Safety Issue: | |
| Description: | Progressive splenomegaly is assessed by increasing spleen volume (by MRI/CT) of ≥ 25% from baseline. Accelerated phase: 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 x 10^9/L that lasts for at least 4 weeks. Leukemic transformation, 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%. |
| Measure: | Proportion of subjects achieving an impovement in bone marrow fibrosis of ≥ 1 grade from baseline |
| Time Frame: | Baseline to the end of Cycle 6 or 8 (24 weeks), the end of Cycle 12 or 16 (48 weeks) and at the end of treatment if not performed in the past 12 weeks (up to 48 weeks) |
| Safety Issue: | |
| Description: | Proportion of subjects achieving an improvement in bone marrow fibrosis of >= 1 grade at each time point will be summarized in Part 2 and Part 3 of the study. |
| Measure: | Area under the Plasma Concentration versus Time Curve (AUC) |
| Time Frame: | Days 1 and 5 of Cycle 1 and 2 for siremadlin and ruxolitinib, and Cycle 1 and Cycle 3 for crizanlizumab, sabatolimab and NIS793, and Days 1 and 15 of Cycle 1 for LTT462 |
| Safety Issue: | |
| Description: | AUC for each investigational drug in Part 1, Part 2 and Part 3 of the study |
| Measure: | Maximum (peak) observed plasma drug concentration (Cmax) |
| Time Frame: | Days 1 and 5 of Cycle 1 and 2 for siremadlin and ruxolitinib, and Cycle 1 and Cycle 3 for crizanlizumab, sabatolimab and NIS793, and Days 1 and 15 of Cycle 1 for LTT462 |
| Safety Issue: | |
| Description: | Cmax for each investigational drug in Part 1, Part 2 and Part 3 of the study |
| Measure: | Time to reach maximum (peak) plasma, blood, serum or other body fulid drug concentration after single dose administration (Tmax) |
| Time Frame: | Days 1 and 5 of Cycle 1 and 2 for siremadlin and ruxolitinib, and Cycle 1 and Cycle 3 for crizanlizumab, sabatolimab and NIS793, and Days 1 and 15 of Cycle 1 for LTT462 |
| Safety Issue: | |
| Description: | Tmax for each investigational drug in Part 1, Part 2 and Part 3 of the study |
| Measure: | Concentration versus time profile |
| Time Frame: | Days 1 and 5 of Cycle 1 and 2 for siremadlin and ruxolitinib, and Cycle 1 and Cycle 3 for crizanlizumab, sabatolimab and NIS793, and Days 1 and 15 of Cycle 1 for LTT462 |
| Safety Issue: | |
| Description: | Concentration versus time profile for each investigational drug in Part 1, Part 2 and Part 3 of the study |
| Measure: | Presence and/or concentration of anti-drug antibody |
| Time Frame: | Baseline to 105 days after last study drug administration for crizanlizumab, to 150 days after last study drug administration for sabatolimab, or to 90 days after last study drug administration for NIS793 |
| Safety Issue: | |
| Description: | The presence and titer of anti-drug antibodies for crizanlizumab, sabatolimab and NIS793 in Part 1, Part 2 and Part 3 of the study |
| Phase: | Phase 1/Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Novartis Pharmaceuticals |
July 2, 2021
