| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) |
|
| E.1.1.1 | Medical condition in easily understood language |
MDS: disorders
where bone marrow produces fewer/immature blood cells
AML: cancer of the white blood cells (myeloid cells) |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000886 |
| E.1.2 | Term | Acute myeloid leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10028536 |
| E.1.2 | Term | Myelodysplastic syndromes |
| E.1.2 | System Organ Class | 100000004851 |
|
| 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 |
| Evaluate the efficacy of subcutaneous (sc) azacitidine in combination with durvalumab as compared with subcutaneous azacitidine alone in the defined study population. |
|
| E.2.2 | Secondary objectives of the trial |
Safety: Assess the safety and tolerability of subcutaneous (sc) azacitidine in combination with durvalumab compared with subcutaneous azacitidine alone in the defined study population.
Pharmacokinetics: To assess the pharmacokinetics (PK) of durvalumab when given in combination with subcutaneous azacitidine in the defined study population. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For both cohorts:
1. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
2. Have an ECOG performance status of 0, 1, or 2.
3. Female subjects of childbearing potential may participate, providing they meet the following conditions:
a. Have 2 negative pregnancy tests as verified by the Investigator prior to starting any IP therapy: serum pregnancy test at screening and negative serum or urine pregnancy test (Investigator’s discretion) within 72 hours prior to starting treatment with IP (Cycle 1, Day 1). 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 practices complete 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 a highly effective method 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 interruptions) 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 the last dose of IP.
d. Refrain from egg cell donation while taking durvalumab and for at least 90 days after the last dose of durvalumab.
4. Male subject 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 methods of contraception, to use male condom plus spermicide during sexual contact with a pregnant female or a female of childbearing potential (even if he has undergone a successful vasectomy) from starting dose of IP (Cycle 1 Day 1), including dose interruptions 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.
5. Understand and voluntarily sign a biomarker-specific component of the informed consent form prior to any study-related procedures conducted.
6. Willing and able to adhere to the study visit schedule and other protocol requirements.
MDS Cohort:
7. Age ≥ 18 years at the time of signing the informed consent form.
8. Central confirmation of diagnosis of previously untreated primary or secondary MDS as per WHO classification. Results of central pathology review are required prior to receiving the first dose of IP.
9. Central confirmation of the categorization of the MDS risk classification, as per the IPSS-R Intermediate risk with >10% blasts or poor or very poor cytogenetics, or IPSS-R High or Very High risk (Results of central pathology review required prior to receiving the first dose of IP).
AML Cohort:
10. Age ≥ 65 years at the time of signing the informed consent form (ICF).
11. Central confirmation of diagnosis of one of the following untreated AML as per WHO classification:
· Newly diagnosed, histologically confirmed de novo AML (bone marrow blasts ≥ 20%), or
· AML secondary to prior MDS, or
· AML secondary to exposure to potentially leukemogenic therapies or agents (eg, radiation therapy, alkylating agents, topoisomerase II inhibitors) with the primary malignancy in remission for at least 2 years.
12. Central confirmation of intermediate or poor risk status, based on Cytogenetics for Acute Myeloid Leukemia.
|
|
| E.4 | Principal exclusion criteria |
For both cohorts:
1. Prior hematopoietic stem cell transplant.
2. Considered eligible for hematopoietic stem cell transplant (allogeneic or autologous).
3. Prior exposure to azacitidine, decitabine or prior exposure to the investigational oral formulation of decitabine, or other oral azacitidine derivative.
4. Inaspirable bone marrow.
5. Use of any of the following within 28 days prior to the first dose of IP:
· Thrombopoiesis-stimulating agents
· Any hematopoietic growth factors
· Any investigational agents within 28 days or 5 half-lives (whichever is longer) of initiating study treatment
6. Prior history of malignancies, (except MDS for AML subjects), unless the subject has been free of the disease for ≥ 2 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.
7. Pregnant or breast-feeding females or females who intend to become pregnant during study participation.
8. Subject has active or prior documented autoimmune or inflammatory disorders within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:
· Subjects with vitiligo or alopecia;
· Subjects with hypothyroidism stable on hormone replacement for ≥ 3 months prior to signing the ICF; or
· Subjects with psoriasis not requiring systemic treatment
9. Significant active cardiac disease within the previous 6 months prior to signing the ICF
10. Uncontrolled intercurrent illness.
11. Known HIV or HCV infection, or evidence of active HBV infection.
12.Known or suspected hypersensitivity to azacitidine, mannitol, or durvalumab, its constituents, or to any other humanized mAb.
13. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
14. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
15. Prior anti-CTLA-4, PD-1, or PD-L1 or other immune checkpoint mAb exposure.
16. Other investigational mAbs within 6 months prior to first dose of IP.
17. Current or prior use of immunosuppressive medication within 14 days prior to the first dose of IP. The following are exceptions:
· Intranasal, inhaled, topical, or local steroid injections
· Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent
· Steroids as premedication for hypersensitivity reactions
18. History of primary immunodeficiency.
19. Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP.
20. Unwilling or unable to complete subject reported outcome assessments without assistance or with minimal assistance from trained site personnel and/or caregiver.
21. Subjects who have had clinical evidence of CNS or pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia.
22. Presence of advanced malignant hepatic tumors.
23. Any of the following laboratory abnormalities:
· AST/SGOT or ALT/SGPT > 2.5 × ULN
· Serum total bilirubin > 1.5 × ULN. Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow. 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 × ULN.
MDS Cohort:
24. Any previous cytotoxic, cytostatic, hormonal, biological or immunological treatment for MDS.
25. Any investigational therapy within 28 days prior to the first dose of IP.
26. Use of hydroxyurea within 2 weeks prior to obtaining the screening hematology sample and prior to first dose of IP.
27. Absolute WBC count ≥ 15 × 109/L.
AML Cohort:
28. Previous cytotoxic, cytostatic, hormonal, biological or immunological treatment or biologic treatment for AML.
29. Any investigational therapy within 28 days prior to the first dose of IP.
30. Use of hydroxyurea within 2 weeks prior to obtaining the screening hematology sample and prior to first dose of IP.
31. Prior use of targeted therapy agents.
32. Suspected or proven acute promyelocytic leukemia (FAB M3) based on morphology, immunophenotype, molecular assay, or karyotype; AML associated with t(9;22) karyotype, biphenotypic acute leukemia or AML with previous hematologic disorder such as chronic myelogenous leukemia or myeloproliferative neoplasms.
33. Acute myeloid leukemia associated with inv(16), t(8;21), t(16;16), t(15;17) karyotypes or molecular evidence of such translocations if not associated with a c-kit mutation.
34. Absolute WBC count ≥ 15 × 109/L.
35. Known history or presence of Sweet Syndrome at screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
MDS Cohort:
- Overall response rate (defined as CR, PR, mCR and/or HI) using the IWG 2006 response criteria for MDS
AML Cohort:
- Overall response rate (CR or CRi) based on modified IWG 2003 response criteria for AML |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| IWG Response Assessment based on IWG criteria for MDS and modified IWG criteria for AML is to be performed every 3 cycles of treatment during the first 6 treatment cycles. Subjects who continue beyond Cycle 6 will have IWG response assessment following every 3 treatment cycles. The assessment must be performed prior to beginning Day 1 procedures for the subsequent treatment cycle (Cycle 4, 7, 10, etc). |
|
| E.5.2 | Secondary end point(s) |
MDS Cohort:
1- Time to response
2- Relapse-free survival
3- Cytogenetic response
4- Progression-free survival (PFS)
5- Duration of response
6- Time to AML transformation
7- Transformation to AML
AML Cohort:
1- Time to response
2- Relapse-free survival
3- Complete cytogenetic response (CyCR)
4- Hematologic Improvement Rate
5- Duration of response
Phase 2: Both Cohorts:
1- Safety
2- Overall survival
3- One-year survival
4- PK parameters |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
MDS
1-C1D1 to CR,PR or mCR
2-CR,PR or mCR until relapse,death or loss to FU
3-C1D1 to documentation of CyCR or partial cytogenetic response
4-C1D1 to progression or death
5-CR,PR or mCR until relapse or PD
6-C1D1 until date of transformation to AML
7-Ongoing
AML
1-C1D1 to response
2-CR or CRi until relapse,death or loss to FU
3-C1D1 until CyCR
4-C1D1 to rate of Neutrophil response+Eythroid response+Platelet response
5-Time from first CR/CRi until relapse, PD or death
Both
1-Ongoing incl FU
2-C1D1 to death
3-Prob of survival at 1 year from randomisation
4-C1D1 end of infusion;C2D1 preinfusion(-90m to -5m prior to dose);C4D1 preinfusion(-90m to -5m prior to dose) and end of infusion;C6D1 preinfusion(-90m to -5m prior to dose);Safety FU (90d after last dose of MEDI4736)
|
|
| 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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity analysis, Biomarker analysis |
|
| 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 | Yes |
| 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 | Yes |
| 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 | No |
| 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 | 80 |
| 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 |
| Austria |
| Belgium |
| Canada |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| 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
|
| The End of Trial is defined as either the date of the last subject last visit for the completion of posttreatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, 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 | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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