| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Myelodysplastic syndrome (MDS) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Umbrella term for disorders of the bone marrow, leading to a reduced number of red blood cells. |
|
| 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 | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068361 |
| E.1.2 | Term | MDS |
| 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 |
| The primary objective of this study is to investigate the efficacy of CC-486 in subjects with MDS that did not respond to prior treatment with an injectable hypomethylating agent (HMA –azacitidine for injection or decitabine), or who were unable to tolerate treatment with an injectable HMA. |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the safety and tolerability of CC-486 as treatment for MDS
- To describe the clinical relevance of objective hematologic and/or biologic responses associated with treatment with CC-486 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female, ≥ 18 years of age at the time of signing the informed consent document.
2. Documented diagnosis of myelodysplastic syndromes (MDS), classified according to French-American British (FAB) cooperation group classification criteria.
3. Adequate course of treatment with an injectable hypomethylating agent (azacitidine for injection or decitabine) as the last therapeutic intervention for myelodysplastic syndromes prior to beginning screening for this study.
4. Documented disease progression or stable disease as best response to treatment (or attempted treatment) with azacitidine for injection or decitabine.
5. Have the last dose of the prior treatment regimen (injectable hypomethylating agent (HMA) – azacitidine for injection or decitabine) not more than 12 weeks prior to screening for this study.
6. No less than 3 weeks between the last dose of the prior treatment regimen (injectable HMA – azacitidine for injection or decitabine) and the planned date of first dose of investigative product.
7. Have an Eastern Oncology Cooperative Group (ECOG) performance status of 0, 1, or 2.
8. Females of childbearing potential may participate, providing they meet the following conditions:
- Agree to use at least two effective contraceptive methods; and
- Have a negative serum pregnancy test at screening; and
- Have a negative serum or urine pregnancy test within 72 hours prior to starting treatment with investigative product and before beginning each subsequent cycle of treatment.
9. Male subjects with a female partner of childbearing potential must agree to use at least two physician-approved contraceptive methods throughout the course of the study and should avoid fathering a child during the course of the study and for 3 months following the last dose of investigational product.
10. Understand and voluntarily sign an informed consent document prior to any study related assessments or procedures are conducted.
11. Be able to adhere to the study visit schedule and other protocol requirements. |
|
| E.4 | Principal exclusion criteria |
1. Rapidly-progressing myelodysplastic syndromes (MDS)
2. Acute myelogenous leukemia (AML) – French-American British (FAB) cooperation group classification: ≥ 30% blasts in bone marrow). Subjects known to have ≥ 30% blasts are not eligible for inclusion in this study. Recognizing limitations of blast cell quantification, this protocol will allow subjects with pre-enrollment (screening/baseline) bone marrow blast counts up to 33% to be considered for inclusion.
3. Prior allogeneic or autologous stem cell transplant.
4. Prior exposure to the investigational oral formulation of decitabine.
5. Prior or ongoing response (International Working Group 2006 Hematologic Improvements (HI), Partial Response (PR), Complete Response (CR), or marrow Complete Responses) to treatment with azacitidine for injection or decitabine, including relapsed disease.
6. Ongoing medically significant adverse events from previous treatment, regardless of the time period.
7. Use of any of the following within 28 days prior to the first dose of investigational product:
- thrombopoiesis-stimulating agents ([TSAs]; e.g., Romiplostim, Eltrombopag, Interleukin-11)
- Erythropoietin stimulating agents (ESAs) and other red blood cell hematopoietic growth factors (e.g., Interleukin-3)
- hydroxyurea
8. Concurrent use of corticosteroids unless the subject is on a stable or decreasing dose for ≥ 1 week prior to enrollment for medical conditions other than myelodysplastic syndromes (MDS)
9. History of inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis), celiac disease (i.e., sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism or excretion of the investigational product and/or predispose the subject to an increased risk of gastrointestinal toxicity.
10. Prior history of malignancies, other than myelodysplastic syndromes, unless the subject has been free of the disease for ≥ 3 years. However, subjects with the following history/concurrent conditions are allowed:
- Basal or squamous cell carcinoma of the skin
- Carcinoma in situ of the cervix
- Carcinoma in situ of the breast
- Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system)
11. Significant active cardiac disease within the previous 6 months
12. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment)
13. Known Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection, or evidence of active Hepatitis B Virus (HBV) infection
14. Any of the following laboratory abnormalities:
- Serum aspartate transaminase (AST)/serum glutamic oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamic pyruvate transaminase (SGPT) > 2.5 x upper limit of normal (ULN)
- Serum total bilirubin > 1.5 x upper limit of normal (ULN). Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (i.e., ineffective erythropoiesis). Subjects are excluded if there is evidence of autoimmune hemolytic anemia manifested as a corrected reticulocyte count of > 2% with either a positive Coombs’ test or over 50% of indirect bilirubin
- Serum creatinine > 2.5 x upper limit of normal (ULN)
- Absolute white blood cell (WBC) count ≥ 20 x 10*9/L
15. Known or suspected hypersensitivity to azacitidine or mannitol
16. Pregnant or lactating females
17. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
18. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
19. Any condition that confounds the ability to interpret data from the study, including known or suspected conditions other than myelodysplastic syndromes (MDS), associated with anemia |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Overall rate of objective response (ORR) to treatment with CC-486
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| - Evaluated following Cycles 2, 4, 6 and every 3 cycles thereafter, as well as upon treatment discontinuation. |
|
| E.5.2 | Secondary end point(s) |
- overall survival (OS)
- time to onset of responses
- duration of responses
- progression free survival (PFS)
- proportion of subjects with progressive disease at Baseline achieving Stable Disease (SD), as well as time to achieving stable disease and duration of stable disease (SD and Time to/Duration of Response)
- the proportion of subjects progressing to Acute Myeloid Leukemia (AML) and time to AML progression (AML Progression)
- Safety and Tolerability |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Time to onset of responses, Duration of Responses, SD, Time to SD, Duration of SD: Evaluated following Cycles 2, 4, 6 and every 3 cycles thereafter, as well as upon treatment discontinuation.
- OS, AML, Time to AML, PFS: continuously throughout the study until death, loss-to follow-up, withdrawal of consent, or study closure.
- Safety and Tolerability: continuously throughout the course of treatment until 28 days after the last dose of the Investigational Product or the last study visit, whichever date is later. |
|
| 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 | Yes |
| 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 | No |
| 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 |
|
| 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
|
| Either the date of the LVLS to complete the study, or the date of receipt of the last data point from the last patient that is required for primary, secondary and/or exploratory analysis, as pre-specified in the protocol and/or the Statistical Analysis Plan, whichever is the later date. |
|
| 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 | 19 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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