E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Myelofibrosis (MF) is classified as a myeloproliferative neoplasm (MPN) |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 18.0 |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objectives of this study are to evaluate spleen response rate and symptom response rate of 2 dose regimens of imetelstat (9.4 mg/kg and 4.7 mg/kg imetelstat given intravenous [IV] every 3 weeks) in subjects with intermediate-2 or high-risk MF who are relapsed after or refractory to JAK inhibitor treatment. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
- To assess the safety of imetelstat
- To assess CR or PR, CI, spleen response, symptoms response, and anemia response per modified 2013 IWG-MRT criteria, duration of responses, and overall survival (OS).
- To evaluate the pharmacokinetics of imetelstat
- To evaluate the PK/response and pharmacodynamic (PD) relationships with factors that include hemoglobin concentration, spleen size, and platelet count
- To evaluate the immunogenicity of imetelstat
- To assess the effect of treatment on PROs (patient-reported outcomes) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Diagnosis of PMF according to the revised WHO criteria; or PET-MF or PPV-MF according to the IWG-MRT criteria
- DIPSS intermediate-2 or high risk MF
- Measurable splenomegaly prior to study entry as demonstrated by palpable spleen measuring greater than or equal to (>=) 5 cm below the left costal margin OR spleen volume of >= 450 cm^3 measured by MRI
- Active symptoms of MF as demonstrated by a symptom score of at least 5 points (on a 0 to 10 scale) on at least one of the symptoms or a score of 3 or greater on at least 2 of the symptoms
- Documented progressive disease during or after JAK inhibitor therapy
- ECOG performance status 0, 1 or 2 |
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E.4 | Principal exclusion criteria |
- Peripheral blood blast count of >= 10% or bone marrow blast count of >=10%
- Prior treatment with imetelstat
- Major surgery within 4 weeks of randomization
- Past or present active hepatitis infection of any type or known acute or chronic liver disease including cirrhosis
- Prior history of hematopoietic stem cell transplant |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Percentage of participants who Achieve Greater than or equal to 35 percent (%) Reduction in Spleen Volume at Week 24 (Spleen response rate is defined as the percentage of participants who achieve >= 35% reduction in spleen volume at Week 24 from baseline as measured by imaging scans.)
- Percentage of participants who Achieve Greater than or equal to 50 percent (%) Reduction in Total Symptom Score at Week 24 (Symptom response rate is defined as the percentage of participants who achieve >= 50% reduction in TSS at Week 24 from baseline as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) version 2.0 diary.) |
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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) |
- Complete remission (CR) or partial remission (PR) per modified 2013 IWG-MRT criteria
- Clinical improvement (CI) per modified 2013 IWG-MRT criteria
- Number of Participants with Responses per 2013 IWG-MRT (Spleen response, symptoms response, and anemia response per modified 2013 IWG-MRT will be assessed.)
- Duration of Treatment Response and Remission (Duration of spleen response, duration of symptoms response, duration of CR or PR, duration of CI, and duration of anemia response will be reported.)
- Overall Survival (Overall survival is defined as the time from randomization to date of death from any cause.)
- European Organization for Research and treatment of Cancer (EORTC) QLQ-C30 Score
- EuroQol-EQ-5D (EQ-5D-5L) Health Questionnaire Score
- Brief Pain Inventory- Short Form (BPI) Score
- Patient’s Global Impression of Change (PGIC)
- Number of Participants with Adverse Events (AEs)
- Maximum Plasma Concentration (Cmax) of Imetelstat (The Cmax is the maximum observed plasma concentration.)
- Time to Reach Maximum Concentration (tmax) of Imetelstat (The tmax is time to reach the maximum observed plasma concentration.)
- Area Under the Plasma Concentration-Time Curve From Time Zero to 24 Hours (AUC [0-24h]) of Imetelstat (AUC 0-24h is area under the plasma concentration-time curve from time 0 to 24 hours postdose.)
- Elimination Half-Life (t [1/2] Lambda) of Imetelstat (Elimination half-life (t [1/2] Lambda) is associated with the terminal slope (lambda [z]) of the semi logarithmic drug concentration-time curve, calculated as 0.693/lambda(z).) |
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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 | No |
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 |
Immunogenicity
Biomarker
Patient Reported Outcome |
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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 | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | Yes |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 47 |
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 |
Belgium |
Canada |
France |
Germany |
Israel |
Italy |
Korea, Republic of |
Spain |
Switzerland |
Taiwan |
United Kingdom |
United States |
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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 study is considered completed 18 months after the last subject is enrolled or anytime the sponsor terminates the study, whichever comes first. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 9 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 9 |