E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Newly Diagnosed RARA-positive Adult Patients with Higher-risk Myelodysplastic Syndrome |
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E.1.1.1 | Medical condition in easily understood language |
Adult patients with higher-risk Myelodysplastic syndrome (MDS) who have high levels of the RARA biomarker in their blood. |
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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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Characterize and compare the complete remission/complete response rate of tamibaterone plus azacitidine vs. placebo plus azacitidine |
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E.2.2 | Secondary objectives of the trial |
- Characterize and compare the overall survival (OS) of tamibarotene + azacitidine vs. placebo + azacitidine; - Characterize and compare the transfusion independence (TI) rate of tamibarotene + azacitidine vs. placebo + azacitidine; - Characterize and compare the overall response rate (ORR) of tamibarotene + azacitidine vs. placebo + azacitidine; - Characterize the duration of complete response (DOCR) and duration of overall response of tamibarotene + azacitidine or placebo + azacitidine; - Characterize the time to complete remission/complete response (CR) and time to initial response of tamibarotene + azacitidine vs. placebo + azacitidine; - Characterize and compare the event-free survival (EFS) of tamibarotene + azacitidine vs. placebo + azacitidine - Compare changes in helath-related quality of life (HRQOL) of tamibarotene + azacitidine vs. placebo + azacitidine - Characterize the safety of tamibarotene + azacitidine vs. placebo + azacitidine. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients must be at least 18 years old at the time of signing of an informed consent. 2. Patients must be RARA-positive based on the investigational assay. 3. Patients must be newly diagnosed with HR-MDS as follows: Diagnosis of MDS according to the WHO classification (Arber 2016) and classified by the IPSS-R risk category as: a. Very High (risk score >6), b. High (risk score >4.5 to 6), OR c. Intermediate (risk score >3 to 4.5). 4. Patients must have measurable disease with bone marrow blasts >5% at the Screening Visit. 5. Patients must have ECOG Performance Status of ≤2. 6. Patients must have adequate organ function, as defined by: a. total bilirubin < or = 3.0 × the ULN, b. ALT and AST < or = 3 × ULN, and c. creatinine clearance > or = 30 mL/min based on the Cockcroft-Gault Glomerular Filtration Rate estimation. 7. Patients must have a serum/high-sensitivity urine pregnancy test (for females of childbearing potential) that is negative at the Screening Visit and immediately prior to initiation of treatment (first dose of study drug). 8. Patients must be willing and able to comply with the scheduled study visits, treatment plans, laboratory tests, use of 2 methods of birth control (including a barrier method) for women of childbearing potential (WOCBP) and male patients, and other procedures. 9. Patients must be capable of giving signed and dated IRB or IEC approved informed consent document. |
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E.4 | Principal exclusion criteria |
1. Patients are suitable for and agree to undergo allogeneic HSCT at the time of screening. 2. Patients received prior treatment for MDS with any hypomethylating agent, chemotherapy (including lenalidomide), or allogeneic HSCT, with the exception of prior treatment with growth factors or hydroxyurea. Growth factor treatment must be discontinued at least 2 weeks prior to starting study drug. Hydroxyurea treatment must be discontinued prior to starting study drug. 3. Patients with history of cancer are excluded if they are in active treatment (with radiation, chemotherapy, antibodies, immunotherapies, or molecularly targeted therapies) or unless they are disease free for at least 2 years prior to the Screening Visit, following completion of a prior treatment. Exceptions include: localized prostate cancer treated with hormone monotherapy; localized breast cancer treated with adjuvant hormone monotherapy; or localized basal cell carcinoma, non-melanoma skin cancer, or cervical carcinoma in situ. 4. Patients have an active, life-threatening, or clinically-significant, uncontrolled systemic infection requiring hospitalization. 5. Patients have a known malabsorption syndrome or other condition that may impair absorption of study medication (e.g., gastrectomy). 6. Immunocompromised patients with increased risk of opportunistic infections, including known HIV-positive patients with CD4 counts < or =350 cells/mm3 or history of opportunistic infection in the last 12 months. Note: To ensure that effective ART, when used in eligible HIV-positive patients, is tolerated and that toxicities are not confused with investigational drug toxicities, patients should be on an established ART for at least 4 weeks and have an HIV viral load less than 400 copies/mL prior to the Screening Visit. 7. Patients have a known active or chronic hepatitis B or active HCV infection. Patients with a history of HCV infection who have completed curative therapy for HCV at least 12 weeks before the Screening Visit and have a documented undetectable viral load at the Screening Visit are eligible for enrollment. 8. Patients have other severe acute or chronic medical conditions (and/or psychiatric conditions or laboratory abnormalities) that may increase the expected risk to the patient (i.e., the risk associated with the study participation or investigational product administration), or that may interfere with the interpretation of study results or, in the judgment of the investigator, would make the patient inappropriate for entry into this study. 9. Patients received prior treatment with ATRA or systemic retinoid for a hematologic malignancy. 10. Patients have not adequately recovered from a major surgery within 4 weeks of starting study drug administration. 11. Patients with a diagnosis of hypervitaminosis A or patients taking vitamin A supplements >10,000 IU/day, unless treatment is discontinued at least 7 days prior to the first dose of the study drug. 12. Patients known to be refractory to platelet or packed red blood cell transfusions per Institutional Guidelines, or patients who refuse blood product support. 13. Patients received strong inducers of CYP3A4 within 2 weeks prior to the first tamibarotene/placebo administration. 14. Patients received any other investigational agents within 4 weeks of the Screening Visit, or <5 half-lives since completion of previous investigational therapy have elapsed, whichever is shorter. 15. Patients require concurrent treatment with any investigational or approved oncology agent, other than the agents described in exclusion criterion #3. 16. Patients with > or = 20% blasts in peripheral blood or bone marrow or evidence of myeloid sarcoma (extramedullary AML). 17. Patients with Grade > or = 2 hypertriglyceridemia, defined as >300 mg/dL (CTCAE, version 5) 18. QTc >450 msec for male patients, QTc >470 msec for female patients, or QTc >480 msec in male or female patients with bundle branch block based on triplicate electrocardiogram (ECG) readings at the Screening Visit. NOTE: The QTc in this study should be the QT interval corrected for heart rate according to Fridericia formula (QTcF). 19. Pregnant females, breastfeeding females, and males not willing to comply with contraceptive requirements or females of childbearing potential not willing to comply with contraceptive requirements. 20. Patients who have a hypersensitivity to tamibarotene, azacitidine, or to any of their excipients 21. Patients for whom treatment with tamibarotene or azacitidine is contraindicated. 22. Patients with clinically significant cardiovascular disease, including unstable angina, acute myocardial infarction within 3 months prior to the start of study drug administration, or New York Heart Association Class III or IV congestive heart failure, cerebral vascular accident within 3 months prior to the start of study drug administration, or cardiac arrhythmia associated with hemodynamic instability. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Complete remission/complete response rate as determined by the investigator per the modified IWG MDS criteria. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Throughout the course of the study |
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E.5.2 | Secondary end point(s) |
- Overall survival (OS), defined as the time from the date of randomization to the date of death due to any cause; - Transfusion independence (TI), defined as a period of at least 56 days with no RBC or platelet transfusion since the date of randomization to the last dose of study drug +30 days, the initiation of post-treatment therapy, or death, whichever occurs first; - Overall response, defined as achieving complete remission/complete response (CR), partial remission/partial response (PR), marrow complete remission/complete response (mCR), or hematologic improvement (HI) as determined by the investigator per the modified IWG MDS criteria; - Duration of complete response, defined as the duration from the date of first documented evidence of complete remission/complete response to the date of documented relapse of disease as determined by the investigator per the modified IWG MDS criteria, or death due to any cause, whichever occurs first; - Duration of overall response defined as the duration from the date of first documented evidence of complete remission/complete response, partial remission/partial response, marrow complete remission/complete response, or hematologic improvement to the date of documented disease progression, relapse of disease as determined by the investigator per the modified IWG MDS criteria, or death due to any cause, whichever occurs first; - Time to complete remission/complete response, defined as the duration from the date of randomization to the date of the first documented evidence of complete remission/complete response as determined by the investigator per the modified IWG MDS criteria; - Time to initial response, defined as the duration from the date of randomization to the date of the first documented evidence of complete remission/complete response, partial remission/partial response, marrow complete remission/complete response, or hematologic improvement as determined by the investigator per the modified IWG MDS criteria; - Event-free survival (EFS), defined as the time from the date of randomization to the date of transformation to AML or death due to any cause, whichever occurs first - Change in Health-related quality of life (HRQOL) as measured by the EORTC QLQ-30 and EQ-5D-5L - Adverse events and changes in clinical laboratory values, electrocardiogram results, and vital sign measurements. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout the course of the study |
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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 | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | Yes |
E.8.2.2 | Placebo | Yes |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 100 |
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 |
Canada |
Israel |
Mexico |
United Kingdom |
United States |
Austria |
Belgium |
Czechia |
France |
Germany |
Hungary |
Italy |
Poland |
Spain |
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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
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The end of the study is defined as the date of the last scheduled procedure shown in the protocol Schedule of Activities for the last patient in the study globally. |
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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 | 10 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 10 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |