E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Anemia in patients with very low, low or intermediate risk myelodysplastic syndromes (MDS) |
Anämie bei Patienten mit myelodysplastischen Syndromen (MDS) mit sehr niedrigem, niedrigem oder mittlerem Risiko |
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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] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028533 |
E.1.2 | Term | Myelodysplastic syndrome |
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 |
To evaluate the proportion of patients who have an erythroid response (HI-E) according to IWG 2018 criteria separately for both independent substudies. |
Erhebung des Anteils der Patienten, die eine erythroide Reaktion (HI-E) haben, gemäss den Kriterien der IWG 2018, getrennt für beide unabhängigen Kohorten. |
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E.2.2 | Secondary objectives of the trial |
- HI-E response duration - Time to HI-E - Hemoglobin changes from baseline - Red blood cell transfusion (RBC) independence ≥ 8 and ≥ 12 weeks - Frequency of RBC transfusions in transfusion dependent patients - Neutrophil and platelet (HI-N and HI-P) responses - Disease progression according to IWG 2018 criteria - Safety and toxcicity profile of CA-4948 - Quality of life (QoL) - Mutational pattern and burden of selected genes and their influence on response
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- Dauer des HI-E-Ansprechens - Zeit bis HI-E - Unabhängigkeit der Erythrozytentransfusion (RBC) ≥ 8 und ≥ 12 Wochen - Häufigkeit von RBC-Transfusionen bei transfusions-abhängigen Patienten - Neutrophilen- und Thrombozytenanprechen (HI-N und HI-P) - Krankheitsprogression nach den Kriterien der IWG 2018 - Sicherheits- und Toxizitätsprofil von CA-4948 - Lebensqualität (QoL) - Mutationsmuster und Belastung ausgewählter Gene und deren Einfluss auf das Ansprechen
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- MDS OR MDS/MPN including MDS/MPN-RS-T, MDS/MPNu, aCML or CMML - IPSS-R up to 3.5: very low/low/intermediate risk disease (MDS); MDS/MPN < 10% bone marrow blasts; CPSS-Score low/intermediate for CMML - Symptomatic anemia - Defined transfusion strategy - No available option of an approved MDS therapy and classification of prior erythropoiesis-stimulating agent (ESA) treatment as follows: + Cohort A: ESA exposed (and refractory or intolerant); + Cohort B: ESA naive AND serum erythropoietin level >200 U/L
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- MDS oder MDS/MPN einschließlich MDS/MPN-RS-T, MDS/MPNu, aCML oder CMML - IPSS-R bis zu 3,5: sehr niedriges, niedriges oder mittleres Risiko (MDS); MDS/MPN < 10% Knochmarksblasten; CPSS-Score bei CMML: niedrig, intermediär - Symptomatische Anämie - Definierte Transfusionsstrategie - Keine verfügbare Option einer zugelassenen MDS-Therapie und Einstufung der vorherigen Behandlung mit Erythropoiese-stimulierenden Agenzien (ESA) wie folgt: + Kohorte A: ESA-exponiert (und refraktär oder intolerant); + Kohort B: ESA naïve UND Serum Erythropoietinlevel >200 U/L
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E.4 | Principal exclusion criteria |
Compliance with major study procedures 1. Inability to swallow and retain oral medications (> 10 pills) 2. Patient does not accept bone marrow sampling 3. Patient does not accept up to weekly peripheral blood sampling
Safety 4. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≥3 5. Inacceptable organ function: a. Serum creatinine >2 × ULN or calculated creatinine clearance < 30 ml/min b. Aspartate aminotransferase (AST) > 2 × ULN OR alanine aminotransferase (ALT) > 2 × ULN c. Total bilirubin >2 × ULN i. exception >3 × ULN in patients with documented Gilbert’s syndrome
Interfering treatments 6. Prior treatment with azacitidine (injectable or oral) or decitabine. 7. The patient medically requires treatment with the following drugs that are forbidden during the trial or was exposed to one of these 14 days before registration: a) Erythropoiesis stimulating agent (ESA) or luspatercept, b) Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) c) Lenalidomide d) Another investigational drug or device, or approved therapy for investigational use 8. Iron chelation therapy 9. Major surgery within 28 days prior to registration.
Concomitant diseases 10. Known human immunodeficiency virus (HIV) infection 11. Active infectious hepatitis (Type B (HBV) or Type C (HCV) 12. Hepatitis virus detectable within 6 months before registration in patients with a history of hepatitis 13. History of other invasive malignancy, unless definitively treated with curative intent, provided it is deemed to be at low risk for recurrence by the treating physician 14. Presence of an acute or chronic toxicity resulting from prior anti-cancer therapy that has not resolved to Grade ≤1 (except anemia and alopecia), as determined by NCI CTCAE v 5.0 15. Known allergy or hypersensitivity to any component of the formulation of CA-4948 used in this study 16. Severe cardiovascular disease
Formal requirements 17. Positive serum pregnancy test in women of childbearing potential 18. Women of childbearing potential and men who partner with a woman of childbearing potential unwilling to use highly effective contraceptive methods for the duration of the study and for 90 days after the last dose of CA-4948 19. Age under 18 years at registration 20. Inability to provide written informed consent (Subject without legal capacity who is unable to understand the nature, scope, significance and consequences of this clinical trial) 21. Simultaneous participation in another interventional clinical trial or participation in any clinical trial involving administration of an investigational medicinal product within 28 days prior registration
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is erythroid response (HI-E) according to IWG 2018 criteria |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 4 cycles CA-4948 treatment. |
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E.5.2 | Secondary end point(s) |
• HI-E response duration • Time to HI-E • Frequency of RBC transfusions in transfusion dependent patients • Neutrophil and platelet (HI-N and HI-P) responses according to IWG 2018 criteria
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- HI-E response duration: from time point of response determination (after start of treatment) until loss of response Time to HI-E: time from start of treatment until HI-E determination |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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 | 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 | 15 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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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 | 42 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 42 |