Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to investigate the safety, pharmacokinetics and preliminary efficacy of combination treatment of ruxolitinib with 5 novel compounds: siremadlin, crizanlizumab, sabatolimab, rineterkib and NIS793 in myelofibrosis (MF) subjects.

Detailed Description
-----------------
This open-label, multi-center, phase Ib/II platform study design consists of 3 parts. Part 1 is a phase Ib dose escalation and safety run-in for the 5 novel agents in combination with ruxolitinib to assess safety, tolerability and to confirm recommended Phase II dose. Dose escalation cohorts are treated with ruxoltinib + siremadlin or ruxolitinib + rineterkib. Safety run in cohorts are treated with either ruxolitinb + sabatolimab, ruxolitinb + crizanlizumab or ruxolitinib + NIS793 Parts 2 and 3 are phase II selection and expansion respectively, to assess preliminary efficacy of the combination treatments from Part 1 that are evaluated as safe and tolerable. The number of combination treatment arms opening in part 2 will depend on the results of Part 1. In Part 2, an interim analysis was planned to determine if combination treatment (s) can be expanded in Part 3. In June 2022, Novartis decided to permanently halt the study enrollment in all ongoing parts (part 1 and part 2) and part 3 (expansion) will not be initiated. With protocol amendment 8, an extension treatment phase of 12 cycles is added in Part 1 to allow access to the combination treatment for ongoing subjects deriving clinical benefit. in consideration of the enrollment halt, Parts 2 and 3 objectives will not be pursued and Part 1 objectives are updated accordingly.

Official Title
-----------------
A Randomized, Open-label, Phase I/II Open Platform Study Evaluating Safety and Efficacy of Novel Ruxolitinib Combinations in Myelofibrosis Patients

Conditions
-----------------
Myelofibrosis

Intervention / Treatment
-----------------
* Drug: Ruxolitinib
* Drug: Siremadlin
* Drug: Crizanlizumab
* Drug: Sabatolimab
* Drug: Rineterkib
* Drug: NIS793


Participation Criteria
=================
Eligibility Criteria
-----------------
Core treatment phase 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 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 Extension treatment phase inclusion criteria: Signed consent for the extension treatment phase ongoing in the core treatment phase demonstrates clinical benefit of treatment in core treatment phase per investigator's assessment. Core treatment phase 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%. has documented severe hypersensitivity reactions/immunogenicity (IG) to a prior biologic product or Received a monoclonal antibody (Ab) or immunoglobulin-based agent within 1 year of screening in NIS793, crizanlizumab or sabatolimab arms, or in rineterkib or siremadlin arms within <=4 weeks of screening or <=5 half-lives whichever is shorter 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. Extension treatment phase Exclusion Criteria: meets any of study treatment discontinuation criteria current evidence of treatment failure per investigator, following treatment in core treatment phase enrolled in another interventional study evidence of non-compliance to study procedures or withdrew consent in core treatment phase currently has unresolved toxicities for which study treatment has been interrupted in the core treatment phase local access to alternative myelofibrosis treatment including those currently under investigation in clinical trials as assessed suitable in the opinion of the investigator. Other protocol-defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This open-label, multi-center, phase Ib/II platform study design consists of 3 parts. Part 1 is a phase Ib dose escalation and safety run-in for the 5 novel agents in combination with ruxolitinib to assess safety, tolerability and to confirm recommended Phase II dose. Parts 2 and 3 are phase II selection and expansion respectively, to assess preliminary efficacy of the combination treatments from Part 1 that are evaluated as safe and tolerable. The number of combination treatment arms opening in part 2 will depend on the results of Part 1. In Part 2, interim analysis was planned to determine if combination treatment (s) can be expanded in Part 3
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Arm 1: Ruxolitinib + Siremadlin<br>Dose escalation of siremadlin added to existing stable dose of ruxolitinib | Drug: Ruxolitinib<br>* 5 mg tablets for oral use<br>* Other names: INC424, Jakavi;Drug: Siremadlin<br>* 10 mg, 20 mg, or 40 mg capsules for oral use<br>* Other names: HDM201;|
| Experimental: Part 1 Arm 2: Ruxolitinib + Crizanlizumab<br>Safety run-in of crizanlizumab added to existing stable dose of ruxolitinib | Drug: Ruxolitinib<br>* 5 mg tablets for oral use<br>* Other names: INC424, Jakavi;Drug: Crizanlizumab<br>* 100 mg/mL concentrate for infusion for intravenous use<br>* Other names: SEG101;|
| Experimental: Part 1 Arm 3: Ruxolitinib + Sabatolimab<br>Safety run-in of Sabatolimab added to existing stable dose of ruxolitinib | Drug: Ruxolitinib<br>* 5 mg tablets for oral use<br>* Other names: INC424, Jakavi;Drug: Sabatolimab<br>* 100 mg/mL or 400 mg/4 mL concentrate for infusion for intravenous use<br>* Other names: MBG453;|
| Experimental: Part 2 Arm 1: Ruxolitinib + Siremadlin<br>Siremadlin added to existing stable dose of ruxolitinib | Drug: Ruxolitinib<br>* 5 mg tablets for oral use<br>* Other names: INC424, Jakavi;Drug: Siremadlin<br>* 10 mg, 20 mg, or 40 mg capsules for oral use<br>* Other names: HDM201;|
| Experimental: Part 2 Arm 2: Ruxolitinib + Crizanlizumab<br>Crizanlizumab added to existing stable dose of ruxolitinib | Drug: Ruxolitinib<br>* 5 mg tablets for oral use<br>* Other names: INC424, Jakavi;Drug: Crizanlizumab<br>* 100 mg/mL concentrate for infusion for intravenous use<br>* Other names: SEG101;|
| Experimental: Part 2 Arm 3: Ruxolitinib + Sabatolimab<br>Sabatolimab added to existing stable dose of ruxolitinib | Drug: Ruxolitinib<br>* 5 mg tablets for oral use<br>* Other names: INC424, Jakavi;Drug: Sabatolimab<br>* 100 mg/mL or 400 mg/4 mL concentrate for infusion for intravenous use<br>* Other names: MBG453;|
| Active Comparator: Part 2 Arm 6: Ruxolitinib monotherapy<br>Existing stable dose of ruxolitinib as control for Part 2 | Drug: Ruxolitinib<br>* 5 mg tablets for oral use<br>* Other names: INC424, Jakavi;|
| Experimental: Part 3 Arm 1: Ruxolitinib + Compound X<br>Compound from Part 2 (to be confirmed) added to existing stable dose of ruxolitinib | Drug: Ruxolitinib<br>* 5 mg tablets for oral use<br>* Other names: INC424, Jakavi;|
| Experimental: Part 3 Arm 2: Ruxolitinib cessation<br>Compound from Part 2 added to existing stable dose of ruxolitinib for 3 cycles followed by compound monotherapy | Drug: Ruxolitinib<br>* 5 mg tablets for oral use<br>* Other names: INC424, Jakavi;|
| Active Comparator: Part 3 Arm 3: Ruxolitinib monotherapy<br>Existing stable dose of ruxolitinib as control for Part 3 | Drug: Ruxolitinib<br>* 5 mg tablets for oral use<br>* Other names: INC424, Jakavi;|
| Experimental: Part 1 Arm 4: Ruxolitinib + Rineterkib<br>Dose escalation of Rineterkib added to existing stable dose of ruxolitinib | Drug: Ruxolitinib<br>* 5 mg tablets for oral use<br>* Other names: INC424, Jakavi;Drug: Rineterkib<br>* 100 mg capsule for oral use<br>* Other names: LTT462;|
| Experimental: Part 1 Arm 5: Ruxolitinib + NIS793<br>Safety run-in of NIS793 added to existing stable dose of ruxolitinib | Drug: Ruxolitinib<br>* 5 mg tablets for oral use<br>* Other names: INC424, Jakavi;Drug: NIS793<br>* 700 mg/7 mL concentrate for intravenous use<br>|
| Experimental: Part 2 Arm 4: Ruxolitinib + Rineterkib<br>Rineterkib added to existing stable dose of ruxolitinib | Drug: Ruxolitinib<br>* 5 mg tablets for oral use<br>* Other names: INC424, Jakavi;Drug: Rineterkib<br>* 100 mg capsule for oral use<br>* Other names: LTT462;|
| Experimental: Part 2 Arm 5: Ruxolitinib + NIS793<br>NIS793 added to existing stable dose of ruxolitinib | Drug: Ruxolitinib<br>* 5 mg tablets for oral use<br>* Other names: INC424, Jakavi;Drug: NIS793<br>* 700 mg/7 mL concentrate for intravenous use<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities within the first 2 cycles | Incidence and severity of dose limiting toxicities within the first 2 cycles (6 or 8 weeks) in Part 1 of the study | Baseline to the end of Cycle 2 (6 or 8 weeks) | 
| Response rate at the end of cycle 6 or cycle 8 | Composite of anemia improvement (hemoglobin level) and no spleen volume progression and no symptom worsening in Part 2 and Part 3 of the study. For a subject to be considered a responder, all three components of the composite have to be fulfilled | Baseline to the end of Cycle 6 or 8 (24 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects achieving an improvement in hemoglobin level of ≥ 1.5 g/dL from baseline | Percentage 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. | Baseline to the end of Cycle 6 or 8 (24 weeks), and end of Cycle 12 or 16 (48 weeks) | 
| Percentage of subjects achieving an improvement in hemoglobin level of at least >= 2.0 g/dL from baseline | Percentage 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. | Baseline to the end of Cycle 6 or 8 (24 weeks), and end of Cycle 12 or 16 (48 weeks) | 
| Change in spleen length from baseline | Change in spleen length measured in centimeters by manual palpation summarized at each time point using descriptive statistics in Part 1 (core and extension), Part 2 and Part 3 of the study | 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) | 
| Change in spleen volume from baseline | Change in spleen volume measured by magnetic resonance imaging (MRI) or computed tomography (CT) from baseline summarized at each time point using descriptive statistics, including proportions of subjects who achieved (i) at least 35% spleen volume reduction and (ii) at least 25% spleen volume reduction at the end of Cycle 6 (or 8 for NIS793 arm) (24 weeks) from baseline and, at the end of Cycle 12 (or 16 in NIS793 arm) (48 weeks) from baseline respectively in Part 1 (core and extension) Part 2 and Part 3 of the study | 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) | 
| Change in symptoms of MFSAF v4.0 from baseline | 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. | 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) | 
| Change in symptoms of EORTC QLQ-C30 from baseline | 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. | 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) | 
| Changes in symptoms in MFSAF v4.0 (Part 1) from baseline | Change in total symptom scores (TSS) assessed by the Myelofibrosis (MF Symptom Assessment Form version 4.0 (MFSAF v4.0) from baseline including proportion of subjects who achieved at least 50% reduction. | Baseline to end of Cycle 3 or 4 (week 16), and end of Cycle 6 or 8 (week 24weeks), or end Cycle 12 or 16 (48 weeks) | 
| Progression free survival, per progressive splenomegaly, accelerated phase, deteriorating cytopenia, leukemic transformation or death from any cause | 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%. | 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 | 
| Percentage of subjects achieving an improvement in bone marrow fibrosis of ≥ 1 grade from baseline | Percentage 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. | 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) | 
| Area under the Plasma Concentration versus Time Curve (AUC) | AUC for each investigational drug in Part 1, Part 2 and Part 3 of the study | 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 | 
| Maximum (peak) observed plasma drug concentration (Cmax) | Cmax for each investigational drug in Part 1, Part 2 and Part 3 of the study | 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 | 
| Time to reach maximum (peak) plasma, blood, serum or other body fluid drug concentration after single dose administration (Tmax) | Tmax for each investigational drug in Part 1, Part 2 and Part 3 of the study | 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 | 
| Concentration versus time profile | Concentration versus time profile for each investigational drug in Part 1, Part 2 and Part 3 of the study | 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 | 
| Presence and/or concentration of anti-drug antibody | The presence and titer of anti-drug antibodies for crizanlizumab, sabatolimab and NIS793 in Part 1, Part 2 and Part 3 of the study | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ruxolitinib, INC424, siremadlin, HDM201, crizanlizumab, SEG101, myelofibrosis, sabatolimab, MBG453, rineterkib, LTT462, NIS793, platform study