| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with essential thrombocythemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| ET is a type of myeloproliferative neoplasm (diseases of the bone marrow) characterized by the overproduction of platelets. Patients have a high-risk of blood clots and bleeding. |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10015494 |
| E.1.2 | Term | Essential thrombocythemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
To evaluate the safety, efficacy and pharmacodynamics of IMG-7289 when administered orally on a daily basis to patients with essential thrombocythaemia. Safety and tolerability will be evaluated by clinical assessments of safety parameters i.e. safety laboratory testing, adverse event reporting, physical examination and vital sign assessments.
Efficacy and pharmacodynamics will be evaluated by the reduction in platelet counts due to treatment with IMG-7289.
Patients who meet this primary objective will be those who reach the target platelet count of ≤ 400 k/μL (400 x 109/L)
without any new thromboembolic events. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all of the applicable criteria to be eligible for enrollment in this study:
1. Age ≥ 18 years.
2. Diagnosis of Essential Thrombocythemia per World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasms (Arber et al., 2016).
3. Patients who have failed at least one standard therapy (failure is the equivalent of inadequate response or intolerance). European Leukemia Net (ELN) criteria for intolerance / resistance to hydroxyurea (Appendix 16.8) may be used in association with Investigator discretion. Ruxolitinib refractoriness or intolerance will be left to the discretion of the Investigator.
4. Requires treatment in order to lower platelet count based on patient age over 60 or history of thrombosis.
5. Platelet count > 450 k/μL (450 x 109/L) pre-dose Day 1.
6. Peripheral blast count < 1% pre-dose Day 1.
7. ANC ≥ 0.5 x 109/L pre-dose Day 1.
8. Fibrosis Score < grade 2, as per a slightly modified version (Arber et al., 2016) of the European Consensus Criteria for Grading Myelofibrosis, (Thiele et al., 2005).
9. Life expectancy > 36 weeks.
10. Able to swallow capsules.
11. Amenable to bone marrow evaluations and peripheral blood sampling during the study.
12. Must have discontinued ET therapy at least 1 week (4 weeks for interferon) prior to study drug initiation.
13. Women of childbearing potential (WOCBP) and fertile men (see Section 6.1.) must agree to use an approved method of contraception from Screening until 14 days* after last IMG-7289 dose. Methods of contraception include: estrogen and progestogen combined hormonal contraception which inhibits ovulation; progestogen-only hormonal contraception associated with inhibition of ovulation; intrauterine device (IUD); bilateral tubal occlusion; vasectomized partner in a monogamous sexual relationship (vasectomy or tubal ligation at least six months prior to dosing); and, complete sexual abstinence (defined in Section 6.1). Males with a pregnant partner must agree to use a condom to avoid exposure to the developing child. Patients practicing abstinence must agree to use an approved method of contraception should they become sexually active during the study.
*The risk of embryofetal toxicity is fully mitigated by 28 days which is >10 half-lives of the drug at the doses used in this study. |
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria:
1. Hemoglobin < 10 g/dL prior to dosing on Day 1.
2. Transfusion dependency, defined as requiring 2 or more units of pack red blood cells per month for more than 3 months, or a hemoglobin level of ≤8g/dL in the preceding 8 weeks before the start of dosing.
3. Eastern Cooperative Oncology Group (ECOG) questionnaire score of 3 or greater at Screening.
4. History of splenectomy.
5. Has undergone major surgery ≤4 weeks prior to starting study drug or has not recovered from side effects of such surgery.
6. Unresolved treatment related toxicities from prior therapies (unless resolved to ≤ Grade 1).
7. Uncontrolled active infection.
8. Known positive for HIV if not well-controlled (i.e., undetectable viral load) or infectious hepatitis, type A, B or C.
9. Current use of monoamine oxidase A and B inhibitors (MAOIs).
10. Evidence at the time of screening of increased risk of bleeding, including any of the following:
• Activated partial thromboplastin time (aPTT) > 1.3 x the upper limit of normal
• International normalized ratio (INR) >1.3 x the local upper limit of normal
• History of severe thrombocytopenia or platelet dysfunction unrelated to a myeloproliferative disorder or its treatment
• Known bleeding disorder (e.g., dysfibrinogenaemia, factor IX deficiency, haemophilia, Von Willebrand’s disorder, Disseminated Intravascular Coagulation [DIC], fibrinogen deficiency, or other clotting factor deficiency).
11. Evidence at the time of Screening of significant renal or hepatic insufficiency (unless due to haemolysis, or leukaemic infiltration) as defined by any of the following local lab parameters:
• Calculated glomerular filtration rate (GFR; using the Cockcroft-Gault equation) <40 mL/min or serum creatinine > 1.5 x the local upper limit of normal
• Aspartate transaminase (AST) or alanine aminotransferase (ALT) ≥2 x the local upper limit of normal
12. Current use of a prohibited medication (e.g., romiplostim) or expected to require any of these medications during treatment with the investigational drug.
13. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to IMG-7289 or LSD1 inhibitors (i.e., monoamine oxidase inhibitors; MAOIs) that contraindicates their participation.
14. History of any illness/impairment of gastrointestinal (GI) function that might interfere with drug absorption (e.g., chronic diarrhea), confound the study results or pose an additional risk to the patient by participation in the study; patients with gastric bypass surgery.
15. Use of an investigational agent within less than 14 days, or the equivalent of at least 7 half-lives of that agent, whichever is the longer, prior to the study Day 1.
16. Females who are pregnant or breastfeeding or plan to become pregnant or breastfeed during the study.
17. A concurrent second active and non-stable malignancy (patients with a concurrent second active but stable malignancy, such as nonmelanoma skin cancers, are eligible). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• The safety and tolerability of IMG-7289 will be assessed by the analysis of adverse events (AEs), as well as changes in physical examinations, vital signs and laboratory values as detailed below.
o Monitoring of Adverse Events (AEs) including determination of thromboembolic events, dose limiting toxicities (DLTs), serious adverse events (SAEs), and AEs. AEs will be assessed post-first dose until 14 days post-last dose (Note for UK: Non-serious AEs will be assessed post-first dose, and SAEs post consent, until 14 days post-last dose) in terms of onset, duration, seriousness, severity and causality, using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.
o Changes in physical examinations, vital signs and laboratory values will also be evaluated and assessed from Screening/Day 1 until EoS/ET. Information on the timing of these assessments is presented in the schedule of assessment. The following laboratory tests will be conducted:
Complete blood counts (CBC) and differential Coagulation Chemistry panel including LFTs Urinalysis
• The reduction of platelet counts will be evaluated and assessed based on local laboratory measurements of platelet counts from Day 1 to each visit where platelets are measured. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety and Tolerability:
• Adverse events will be assessed from Day 1 (post first dose) up to and including the patient's last study visit.
• Changes in physical examinations, vital signs and laboratory values will be assessed from Screening up to and including the patient's last study visit (End of Study or Early Termination)
Reduction in platelets:
The reduction of platelet counts will be evaluated and assessed based on local laboratory measurements of platelet counts from Day 1 to each visit where platelets are measured. |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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 | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | 1 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Germany |
| Italy |
| New Zealand |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| The End-of-Trial date is considered to be the date of Database Lock. The justification is that the trial only ends when all queries are answered and the database is cleaned. Until that point, sites and/or patients may be called upon for follow up information or clarification of data. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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