Platform Study of Novel Ruxolitinib Combinations in Myelofibrosis Patients (ADORE)
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT04097821 |
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Recruitment Status :
Recruiting
First Posted : September 20, 2019
Last Update Posted : May 24, 2022
|
Sponsor:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
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Brief Summary:
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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Myelofibrosis | Drug: Ruxolitinib Drug: Siremadlin Drug: Crizanlizumab Drug: Sabatolimab Drug: LTT462 Drug: NIS793 | Phase 1 Phase 2 |
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 243 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Masking Description: | Open label |
| Primary Purpose: | Treatment |
| Official Title: | A Randomized, Open-label, Phase I/II Open Platform Study Evaluating Safety and Efficacy of Novel Ruxolitinib Combinations in Myelofibrosis Patients |
| Actual Study Start Date : | September 26, 2019 |
| Estimated Primary Completion Date : | April 16, 2024 |
| Estimated Study Completion Date : | January 23, 2026 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Primary myelofibrosis
| Arm | Intervention/treatment |
|---|---|
|
Experimental: Part 1 Arm 1: Ruxolitinib + Siremadlin
Dose escalation of siremadlin added to existing stable dose of ruxolitinib
|
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi Drug: Siremadlin 10 mg, 20 mg, or 40 mg capsules for oral use
Other Name: HDM201 |
|
Experimental: Part 1 Arm 2: Ruxolitinib + Crizanlizumab
Safety run-in of crizanlizumab added to existing stable dose of ruxolitinib
|
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi Drug: Crizanlizumab 100 mg/mL concentrate for infusion for intravenous use
Other Name: SEG101 |
|
Experimental: Part 1 Arm 3: Ruxolitinib + Sabatolimab
Safety run-in of Sabatolimab added to existing stable dose of ruxolitinib
|
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi Drug: Sabatolimab 100 mg/mL or 400 mg/4 mL concentrate for infusion for intravenous use
Other Name: MBG453 |
|
Experimental: Part 2 Arm 1: Ruxolitinib + Siremadlin
Siremadlin added to existing stable dose of ruxolitinib
|
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi Drug: Siremadlin 10 mg, 20 mg, or 40 mg capsules for oral use
Other Name: HDM201 |
|
Experimental: Part 2 Arm 2: Ruxolitinib + Crizanlizumab
Crizanlizumab added to existing stable dose of ruxolitinib
|
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi Drug: Crizanlizumab 100 mg/mL concentrate for infusion for intravenous use
Other Name: SEG101 |
|
Experimental: Part 2 Arm 3: Ruxolitinib + Sabatolimab
Sabatolimab added to existing stable dose of ruxolitinib
|
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi Drug: Sabatolimab 100 mg/mL or 400 mg/4 mL concentrate for infusion for intravenous use
Other Name: MBG453 |
|
Active Comparator: Part 2 Arm 6: Ruxolitinib monotherapy
Existing stable dose of ruxolitinib as control for Part 2
|
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi |
|
Experimental: Part 3 Arm 1: Ruxolitinib + Compound X
Compound from Part 2 (to be confirmed) added to existing stable dose of ruxolitinib
|
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi |
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Experimental: Part 3 Arm 2: Ruxolitinib cessation
Compound from Part 2 added to existing stable dose of ruxolitinib for 3 cycles followed by compound monotherapy
|
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi |
|
Active Comparator: Part 3 Arm 3: Ruxolitinib monotherapy
Existing stable dose of ruxolitinib as control for Part 3
|
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi |
|
Experimental: Part 1 Arm 4: Ruxolitinib + LTT462
Dose escalation of LTT462 added to existing stable dose of ruxolitinib
|
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi Drug: LTT462 100 mg capsule for oral use |
|
Experimental: Part 1 Arm 5: Ruxolitinib + NIS793
Safety run-in of NIS793 added to existing stable dose of ruxolitinib
|
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi Drug: NIS793 700 mg/7 mL concentrate for intravenous use |
|
Experimental: Part 2 Arm 4: Ruxolitinib + LTT462
LTT462 added to existing stable dose of ruxolitinib
|
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi Drug: LTT462 100 mg capsule for oral use |
|
Experimental: Part 2 Arm 5: Ruxolitinib + NIS793
NIS793 added to existing stable dose of ruxolitinib
|
Drug: Ruxolitinib
5 mg tablets for oral use
Other Name: INC424, Jakavi Drug: NIS793 700 mg/7 mL concentrate for intravenous use |
Primary Outcome Measures :
- Incidence of dose limiting toxicities within the first 2 cycles [ Time Frame: Baseline to the end of Cycle 2 (6 or 8 weeks) ]Incidence and severity of dose limiting toxicities within the first 2 cycles (6 or 8 weeks) in Part 1 of the study
- Response rate at the end of cycle 6 or cycle 8 [ Time Frame: Baseline to the end of Cycle 6 or 8 (24 weeks) ]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
Secondary Outcome Measures :
- 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) ]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.
- 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) ]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.
- 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) ]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
- 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) ]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
- 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) ]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.
- 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) ]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.
- 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 ]
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%.
- 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) ]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.
- 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 ]AUC for each investigational drug in Part 1, Part 2 and Part 3 of the study
- 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 ]Cmax for each investigational drug in Part 1, Part 2 and Part 3 of the study
- 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 ]Tmax for each investigational drug in Part 1, Part 2 and Part 3 of the study
- 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 ]Concentration versus time profile for each investigational drug in Part 1, Part 2 and Part 3 of the study
- 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 ]The presence and titer of anti-drug antibodies for crizanlizumab, sabatolimab and NIS793 in Part 1, Part 2 and Part 3 of the study
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
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.
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04097821
Contacts
| Contact: Novartis Pharmaceuticals | 1-888-669-6682 | novartis.email@novartis.com | |
| Contact: Novartis Pharmaceuticals | +41613241111 |
Locations
| Australia, South Australia | |
| Novartis Investigative Site | Recruiting |
| Adelaide, South Australia, Australia, 5000 | |
| Australia, Victoria | |
| Novartis Investigative Site | Recruiting |
| Melbourne, Victoria, Australia, 3000 | |
| Novartis Investigative Site | Recruiting |
| Melbourne, Victoria, Australia, 3004 | |
| Austria | |
| Novartis Investigative Site | Recruiting |
| Linz, Austria, A-4010 | |
| Belgium | |
| Novartis Investigative Site | Recruiting |
| Leuven, Belgium, 3000 | |
| Canada, Ontario | |
| Novartis Investigative Site | Recruiting |
| Toronto, Ontario, Canada, M5G 2M9 | |
| Canada, Quebec | |
| Novartis Investigative Site | Recruiting |
| Montreal, Quebec, Canada, H1T 2M4 | |
| China, Tianjin | |
| Novartis Investigative Site | Recruiting |
| Tianjin, Tianjin, China, 300020 | |
| Denmark | |
| Novartis Investigative Site | Recruiting |
| Copenhagen, Denmark, 2100 | |
| Germany | |
| Novartis Investigative Site | Recruiting |
| Mannheim, Baden-Wuerttemberg, Germany, 68305 | |
| Novartis Investigative Site | Recruiting |
| Chemnitz, Germany, 09113 | |
| Novartis Investigative Site | Recruiting |
| Freiburg, Germany, 79106 | |
| Novartis Investigative Site | Recruiting |
| Greifswald, Germany, 17475 | |
| Novartis Investigative Site | Recruiting |
| Hamm, Germany, D 59063 | |
| Novartis Investigative Site | Recruiting |
| Jena, Germany, 07740 | |
| Novartis Investigative Site | Recruiting |
| Luebeck, Germany, 23538 | |
| Novartis Investigative Site | Recruiting |
| Stuttgart, Germany, 70176 | |
| Hungary | |
| Novartis Investigative Site | Recruiting |
| Budapest, HUN, Hungary, 1083 | |
| Novartis Investigative Site | Recruiting |
| Pecs, Hungary, 7623 | |
| Italy | |
| Novartis Investigative Site | Recruiting |
| Firenze, FI, Italy, 50134 | |
| Novartis Investigative Site | Recruiting |
| Milano, MI, Italy, 20122 | |
| Japan | |
| Novartis Investigative Site | Recruiting |
| Bunkyo ku, Tokyo, Japan, 113-8431 | |
| Korea, Republic of | |
| Novartis Investigative Site | Recruiting |
| Seoul, Seocho Gu, Korea, Republic of, 06591 | |
| Netherlands | |
| Novartis Investigative Site | Recruiting |
| Amsterdam, Netherlands, 1081 HV | |
| Novartis Investigative Site | Recruiting |
| Rotterdam, Netherlands, 3015 GD | |
| Romania | |
| Novartis Investigative Site | Recruiting |
| Brasov, Romania, 500365 | |
| Novartis Investigative Site | Recruiting |
| Craiova, Romania, 200136 | |
| Russian Federation | |
| Novartis Investigative Site | Active, not recruiting |
| Moscow, Russian Federation, 125284 | |
| Novartis Investigative Site | Recruiting |
| Moscow, Russian Federation, 127644 | |
| Novartis Investigative Site | Recruiting |
| Saint Petersburg, Russian Federation, 191024 | |
| Spain | |
| Novartis Investigative Site | Recruiting |
| Malaga, Andalucia, Spain, 29010 | |
| Novartis Investigative Site | Recruiting |
| Salamanca, Castilla Y Leon, Spain, 37007 | |
| Novartis Investigative Site | Recruiting |
| Alicante, Comunidad Valenciana, Spain, 03010 | |
| Novartis Investigative Site | Recruiting |
| Valencia, Comunidad Valenciana, Spain, 46010 | |
| Novartis Investigative Site | Recruiting |
| Las Palmas de Gran Canaria, Spain, 35010 | |
| Novartis Investigative Site | Recruiting |
| Madrid, Spain, 28034 | |
| Novartis Investigative Site | Recruiting |
| Madrid, Spain, 28041 | |
| Sweden | |
| Novartis Investigative Site | Recruiting |
| Stockholm, Sweden, 14186 | |
| Switzerland | |
| Novartis Investigative Site | Recruiting |
| Geneve 14, Switzerland, 1211 | |
| Novartis Investigative Site | Recruiting |
| St. Gallen, Switzerland, 9007 | |
| Novartis Investigative Site | Recruiting |
| Zurich, Switzerland, 8091 | |
| Turkey | |
| Novartis Investigative Site | Recruiting |
| Kocaeli, Turkey, 41380 | |
| Novartis Investigative Site | Recruiting |
| Samsun, Turkey, 55139 | |
| United Kingdom | |
| Novartis Investigative Site | Recruiting |
| London, United Kingdom, SE1 9RT | |
| Novartis Investigative Site | Recruiting |
| Manchester, United Kingdom, M20 4BX | |
| Novartis Investigative Site | Recruiting |
| Oxford, United Kingdom, OX3 7LJ | |
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
| Responsible Party: | Novartis Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT04097821 |
| Other Study ID Numbers: |
CINC424H12201 2019-000373-23 ( EudraCT Number ) |
| First Posted: | September 20, 2019 Key Record Dates |
| Last Update Posted: | May 24, 2022 |
| Last Verified: | May 2022 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent expert panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data is currently available according to the process described on www.clinicalstudydatarequest.com. |
| URL: | https://www.clinicalstudydatarequest.com |
| Studies a U.S. FDA-regulated Drug Product: | No |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
|
myelofibrosis ruxolitinib INC424 siremadlin HDM201 crizanlizumab |
SEG101 sabatolimab MBG453 LTT462 NIS793 platform study |
Additional relevant MeSH terms:
|
Primary Myelofibrosis Myeloproliferative Disorders Bone Marrow Diseases Hematologic Diseases |