E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Bone marrow disorder that disrupts body's normal production of blood cells. The result is extensive scarring in bone marrow, leading to severe anemia, weakness, fatigue and an enlarged spleen. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028537 |
E.1.2 | Term | Myelofibrosis |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Evaluate the effect of navitoclax alone or in combination with ruxolitinib on spleen volume |
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E.2.2 | Secondary objectives of the trial |
- To assess the effect of navitoclax alone or in combination with ruxolitinib on total symptom score (TSS) as assessed by the Myelofibrosis Symptom Assessment Form (MFSAF) version 4.0 diary - To evaluate the effect of navitoclax alone or in combination with ruxolitinib on bone marrow fibrosis - To determine the rate of anemia response associated with navitoclax alone or in combination with ruxolitinib - To describe the safety profile and PK profile observed with navitoclax alone or in combination with ruxolitinib
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Subjects ≥ 18 years of age - Subjects with documented diagnosis of Intermediate or High-risk Primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis - Subjects classified as intermediate-2 or high-risk myelofibrosis, as defined by the Dynamic International Prognostic Scoring System (DIPSS) - Subject must be ineligible due to age, comorbidities, or unfit for unrelated or unmatched donor transplantation or unwilling to undergo stem cell transplantation at time of study entry - ECOG 0, 1, or 2 - Cohort 1a only: Subject must have received ruxolitinib therapy for at least 12 weeks and be currently on a stable dose of ≥ 10 mg twice daily of ruxolitinib for ≥ 8 weeks prior to the 1st dose of navitoclax. - Cohort 1b only: Subject must have received treatment with ruxolitinib for ≥ 24 weeks with lack of efficacy OR for < 24 weeks with documented disease progression while on ruxolitinib OR for ≥ 28 days with intolerance defined as new RBC transfusion requirement - Cohort 2 only: Subject must have received prior treatment with JAK-2 inhibitor therapy for at least 12 weeks OR for ≥ 28 days complicated by development of red blood cell transfusion requirement (at least 2 units/month for 2 months) OR grade ≥ 3 adverse events of thrombocytopenia, anemia, hematoma and/or hemorrhage - Cohort 3 only: Subject must not have received prior treatment with a JAK-2 or BET inhibitor - Subject has splenomegaly defined as spleen palpation measurement ≥ 5 cm below costal margin or spleen volume ≥ 450 cm3 as assessed by MRI/CT - Cohorts 1b and 3 only: Subject has at least 2 symptoms each with a score ≥ 3 or a total score of ≥ 12, as measured by the MFSAF v4.0 on at least 4 out of 7 days during screening prior to study drug dosing - Subject must meet the laboratory parameters (adequate bone marrow, renal and hepatic function) as defined in the protocol. |
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E.4 | Principal exclusion criteria |
- Splenic irradiation within 6 months prior to screening, or prior splenectomy. - Leukemic transformation (> 10% blasts in peripheral blood or bone marrow aspirate/biopsy). - Subject is currently on medications that interfere with coagulation (including warfarin) or platelet function within 3 days prior to the first dose of study drug or during the study treatment period with the exception of low dose aspirin (up to 100 mg/day) and Low-molecular-weight heparin. - Prior therapy with a BH3 mimetic compound or stem cell transplantation. |
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E.5 End points |
E.5.1 | Primary end point(s) |
≥ 35% spleen volume reduction from baseline (SVR35) at Week 24 measured by MRI/CT. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The secondary endpoints are at least 50% reduction in total symptom score from baseline measured by MFSAF 4.0; anemia response; and change in grade of bone marrow fibrosis. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | Information not present in EudraCT |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 4 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 56 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Canada |
Israel |
Japan |
Korea, Republic of |
Russian Federation |
Serbia |
Taiwan |
Turkey |
United States |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end-of-study is defined as the date of the last subject's last visit or date of last follow-up contact, whichever is later. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 6 |