| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Myelodysplastic syndrome (MDS) |
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| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068361 |
| E.1.2 | Term | MDS |
| E.1.2 | System Organ Class | 100000004864 |
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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 |
| The primary objective of this study is to investigate the efficacy of CC-486 as monotherapy, and in combination with anti-PD-L1 monoclonal antibody, durvalumab (MEDI4736), in subjects with MDS that did not respond to treatment with an injectable hypomethylating agent (HMA –azacitidine for injection or decitabine), or were unable to tolerate treatment with an injectable HMA. |
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| E.2.2 | Secondary objectives of the trial |
- Assess the safety and tolerability of CC-486 alone and in combination with durvalumab as treatment for MDS
- Describe the clinical relevance of objective hematologic and/or biologic responses associated with treatment with CC-486 alone and in combination with durvalumab
- Evaluate the impact (if any) of durvalumab on the pharmacokinetics of CC-486 and CC-486 on durvalumab in subjects with MDS |
|
| 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. Those achieving an objective response to treatment regimen with an injectable HMA are excluded from participation in this study.
5. Have the last dose of the prior treatment regimen (injectable hypomethylating agent (HMA) – azacitidine for injection or decitabine) not more than 16 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 subjects of childbearing potential may participate, providing they meet the following conditions:
a) have two negative pregnancy test s as verified by the investigator prior to starting any IP theraphy; serum pregancy test at screening; and negative serum or urine pregnancy test within 72 hours prior to starting treatment with IP. They must agree to ongoing pregnancy testing during the course of the study (before beginning each subsequent cycle of treatment), and after the last dose of any IP. This applies even if the subject practice true abstinence from heterosexual contact.
b) Agree to practice true abstinence (which must be reviewed on a monthly basis and source documented) or agree to the use of highlu effective methods of contraception from 28 days prior to starting durvalumab or azacitidine, and must agree to continue using such precautions while taking durvalumab or azacitidine (including dose interuptions) and for up to 90 days after the last dose of durvalumab or azacitidine. Cessation of contraception after this point should be discussed with a responsible physician.
c) Agree to abstain from breastfeeding during study participation and for at least 90 days after last dose of IP.
d) Refrain from egg cell donation while taking duravlumab and for at least 90 days after the last dose of durvalumab.
9. Male subjects must:
a) Either practice true abstinence from heterosexual contact (which must be reviewed on a monthly basis) or agree to avoid fathering a child, to use highly effective menthods of contraception, male condom plus spermicide during sexual contact with a pregnant female or female of child bearing potential (even if he has undergone a successful vasectomy) from starting dose IP (Cycle 1 Day) including dose interruption through 90 days after receipt of the last dose of durvalumab or azacitidine.
b) Refrain from semen or sperm donation while taking IP and for at least 90 days after the last dose of IP.
10. Understand and voluntarily sign an informed consent document prior to any study-related assessments or procedures conducted.
11. Be able to adhere to the study visit schedule and other protocol requirements.
12. Understand and voluntarily sign a biomarker-specific component of the informed consent document prior to any study-related procedures conducted.
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|
| E.4 | Principal exclusion criteria |
1. Rapidly-progressing MDS
2. AML-FAB 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 stem cell transplant
4. Prior exposure to the investigational oral formulation of decitabine or other oral azacitidine derivative at any time in the subjects prior history
5. Prior or ongoing response (IWG 2006: HI, PR,CR, or marrow CR) to treatment with azacitidine for injection or decitabine, at any time in the subjects prior history, which includes 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 IP:
a) thrombopoiesis-stimulating agents [TSAs]
b) ESAs and other RBC hematopoietic growth factors
c) 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 MDS
9. History of inflammatory bowel disease (eg, Crohn’s disease, ulcerative colitis), celiac disease (ie, 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 IP and/or predispose the subject to an increased risk of gastrointestinal toxicity.
10. Prior history of malignancies, other than MDS, 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 (ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment)
13. Known HIV or HCV infection, or evidence of active HBV infection
14. Any of the following laboratory abnormalities:
- Serum AST/SGOT) or ALT/SGPT > 2.5 x ULN
- Serum total bilirubin > 1.5 x ULN.
- Serum creatinine > 2.5 x ULN
- Absolute WBC) count ≥ 20 x 10*9/L
15. Known or suspected hypersensitivity to azacitidine or mannitol, or durvalumab its constituents, or to any other humanized monoclonal antibody
16. Pregnant planning to become pregnant starting from 28 days prior to receiving CC-486 or durvalumab, throughout your participation in the study, and for at least 90 days following your last dose of study treatment or breast-feeding 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 MDS, associated with anemia
20. Having received any prior MAb against CTLA-4, PD-1, or PD-L1 or having received other investigational MAbs within 6 months
21. Clinical evidence of central nervous system (CNS) or pulmonary leukostasis, or CNS leukemia
22. Current or prior use of immunosuppressive medication within 14 days prior to the first dose of durvalumab. The following are exceptions to this criterion:
a. Intranasal, inhaled, topical or local steroid injections (eg, intra-articular injection);
b. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent;
c. Steroids as premedication for hypersensitivity reactions (eg, computed tomography [CT] scan premedication).
23. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis, Crohn’s disease], diverticulitis with the exception of a prior episode that has resolved or diverticulosis, celiac disease, irritable bowel disease, or other serious gastrointestinal chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener’s syndrome; myasthenia gravis; Graves’ disease; rheumatoid arthritis; hypophysitis, uveitis) within past 3 years prior to the start of treatment
24. History of primary immunodeficiency
25. Receipt of live, attenuated vaccine within 30 days prior to the first dose of durvalumab
26. Active myeloproliferative neoplasms and chronic myelomonocytic leukemia |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Overall rate of objective response (ORR) to treatment with CC-486 monotherapy and combination therapy with CC-486 and durvalumab; the proportion of subjects achieving and objective response (hematologic improvement [HI-], partial response [PR,-] complete remission [CR,-] or marrow CR-) based on modified International Working Group
|
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| 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.
- Analysis of the primary endpoint will be conducted only after all active subjects have completed the modified IWG response assessment following 6 cycles of therapy. |
|
| E.5.2 | Secondary end point(s) |
- Overall survival (OS)
- Time to onset of responses
- Duration of responses
- Progression free survival (time to disease progression or deatch from any cause);
- Proportion of subjects with progressive disease at baseline achieving stable disease, as well as time to achieving stable disease and duration of stable disease;
- The proportion of subjects progressing to Acute Myeloid Leukemia (AML) and time to AML progression;
- Safety and tolerability (type, frequency, severity of AEs and relationship of AEs to CC-486 and /or durvalumab; monitoring for disease progression to AML, as well as immune- and infusion-type reactions);
- Serum/plasma PK paramaters for durvalumab and CC-486 including maximum observed concentration (Cmax), AUC, time to maximum concentration (Tmax), terminal half-life ( t ½), clearance (CL/F) and volume of distribution (Vz/F) |
|
| 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 CC-486 and 90 days after durvalumab 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| 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 |
| Belgium |
| France |
| Germany |
| Italy |
| Poland |
| Spain |
| 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
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 25 |
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