A Study to Compare the Efficacy and Safety of Oral Azacitidine (Oral-Aza, ONUREG®) plus BSC versus Placebo plus BSC in Participants with IPSS-R Low- or Intermediate-risk MDS

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Celgene Corp.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

28 Mar 2023 → ongoing

Decision date (initial)

2023-03-20

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Celgene Corporation

External identifiers

EU CT number

2022-500479-29-00

WHO UTN

U1111-1276-5463

ClinicalTrials.gov

NCT05469737

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

For Part I (Phase 2) The primary objective is to evaluate the safety and efficacy (CR within 6 cycles) of 2 Oral-Aza dose regimens, and to recommend the optimal dose for the Phase 3 study (RP3D) based on the totality of safety, efficacy, PK, and PD data.
For Part II (Phase 3) The primary objective is to evaluate the CR (as defined in the statistical consideration section) within 6 cycles for both study arms

Secondary objectives 16

1. For Part I (Phase 2) - To evaluate and assess OR to Oral-Aza (ORR within 6 cycles, OR duration) and best OR
2. For Part I (Phase 2) - To assess CR duration
3. For Part I (Phase 2) - To evaluate and assess transfusion independence after treatment with Oral-Aza (pRBC-TI rate, pRBC-TI duration)
4. For Part I (Phase 2) - To evaluate and assess transfusion independence after treatment with Oral-Aza (platelet-TI rate, platelet-TI duration)
5. For Part II (Phase 3) - To evaluate and assess transfusion independence after treatment with Oral-Aza: pRBC- TI rate (in the subgroup of transfusion-dependent participants)
6. For Part II (Phase 3) - To evaluate and assess transfusion independence after treatment with Oral-Aza: pRBC-TI duration (in the subgroup of transfusion-dependent participants)
7. For Part II (Phase 3) - To evaluate and assess transfusion independence after treatment with Oral-Aza: platelet TI rate (in the subgroup of transfusion-dependent participants)
8. For Part II (Phase 3) - To evaluate and assess transfusion independence after treatment with Oral-Aza: platelet TI duration (in the subgroup of transfusion-dependent participants)
9. For Part II (Phase 3) - To evaluate and assess duration of RBC transfusion reduction and RBC transfusion reduction rate
10. For Part II (Phase 3) - To assess CR duration
11. For Part II (Phase 3) - To evaluate and assess OR to Oral-Aza (ORR within 6 cycles, OR duration) and best OR
12. For Part II (Phase 3) - To evaluate and assess OS, EFS, time to transformation to AML, and time to subsequent therapy
13. For Part II (Phase 3) - To monitor iron overload
14. For Part II (Phase 3) - To evaluate safety assessments
15. For Part II (Phase 3) - To evaluate and assess health-related quality of life
16. For Part II (Phase 3) - To evaluate and assess health care resource utilization

Conditions and MedDRA coding

International Prognostic Scoring System-Revised (IPSS-R) Low - or Intermediate - risk Myelodysplastic Syndrome (MDS)

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 4

1. Male and female participants must be ≥ 18 years of age at the time of signing the informed consent.
2. Participant has a documented diagnosis of MDS according to WHO 2016 classification that meets IPSS-R classification of low- or intermediate-risk disease (low IPSS-R score: > 1.5 and ≤ 3.0; intermediate IPSS-R score: > 3.0 and ≤ 4.5). For participants in South Korea, the IPSS-R score for inclusion in Part II (Phase 3) is > 1.5 and ≤ 3.5. MDS subtypes may include (MDS with single lineage dysplasia [MDS-SLD], MDS with multilineage dysplasia [MDS-MLD], MDS with ring sideroblasts [MDS-RS] [SLD or MLD], MDS unclassifiable [MDS-U], MDS with excess blasts-1 [MDS-EB1], MDS with deletion of 5q [MDS-del(5q)], therapy related myeloid neoplasm [t-MN]). MDS diagnosis, WHO classification, and IPSS-R risk classification will be prospectively determined by independent central pathology and cytogenetics review, and applicable central laboratory results
3. Participant has at least 1 cytopenia (anemia, thrombocytopenia, or neutropenia) meeting one of the protocol defined criteria.
4. Have an Eastern Cooperative Oncology Group ECOG performance status of 0, 1, or 2.

Exclusion criteria 11

1. Participants with prior malignancies must have 1) an expected median life expectancy of at least 12 months at the time of inclusion and 2) no active treatment of any sort for at least 24 weeks prior to randomization (including but not limited to immunotherapy or targeted therapy).
2. Overlap syndrome (MDS/MPN), CMML, atypical chronic myeloid leukemia (CML), unclassifiable myeloproliferative disorder (MPD), and MDS with moderate to extensive marrow fibrosis (Grade 2 or 3).
3. Significant active cardiac disease within the previous 6 months.
4. Known history of Human Immunodeficiency Virus (HIV) or Hepatitis C Virus (HCV) infection, or evidence of active Hepatitis B Virus (HBV)
5. Participants with an absolute neutrophil count (ANC) of less than 0.5 × 109/L within a week (7 days) of randomization or other laboratory abnormalities as defined in Section 6.2.
6. Prior treatment with azacitidine (any formulation), decitabine, or other hypomethylating agent.
7. Prior treatment with lenalidomide unless the participant received the last dose ≥ 8 weeks prior to randomization.
8. Use of excluded treatment within 35 days prior to randomization as defined in Section 6.2
9. Use of corticosteroid for any medical condition with an average daily dose above 100mg of hydrocortisone or equivalent 1 week prior to randomization
10. Hypoplastic MDS with a marrow cellularity of ≤ 10%
11. Participants diagnosed with MDS-EB2

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. For Part I (Phase 2) - AEs evaluated using NCI CTCAE criteria, v.5.0, including TEAEs, laboratory assessments, and vital signs
2. For Part I (Phase 2) - Achievement of CR per IWG 2006 criteria within 6 cycles
3. For Part II (Phase 3) - Achievement of CR within 6 cycles

Secondary endpoints 16

1. For Part I (Phase 2) - Achievement of OR within 6 cycles (CR, PR, mCR, HI-E, HI-P, H-IN per IWG 2006 criteria), best OR; OR duration
2. For Part I (Phase 2) - CR duration
3. For Part I (Phase 2) - Achievement of 84-day pRBC-TI within 6 cycles; pRBC-TI duration
4. For Part I (Phase 2) - Achievement of 84-day PLT-TI within 6 cycles; PLT-TI duration
5. For Part II (Phase 3) - Achievement of 84-day pRBC-TI within 6 cycles
6. For Part II (Phase 3) - pRBC-TI duration
7. For Part II (Phase 3) - Achievement of 84-day platelet-TI within 6 cycles
8. For Part II (Phase 3) - Platelet-TI duration
9. For Part II (Phase 3) - Achievement of pRBC transfusion reduction; pRBC transfusion reduction duration
10. For Part II (Phase 3) - CR duration
11. For Part II (Phase 3) - Achievement of OR within 6 cycles (CR, PR, mCR, HI-E, HI-P, H-IN per IWG 2006 criteria), best OR; OR duration
12. For Part II (Phase 3) - OS, EFS (event: death, AML, MDS-EB 2), time to AML, time to subsequent therapy
13. For Part II (Phase 3) - Iron parameters
14. For Part II (Phase 3) - AEs evaluated using NCI CTCAE criteria, v.5.0, including TEAEs, laboratory assessments and vital signs
15. For Part II (Phase 3) - Change from baseline in the FACT-An, QUALMS, and EQ-5D-5L
16. For Part II (Phase 3) - Evaluation of healthcare resource use (eg, hospitalization) associated with IP during study

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Celgene Corp.

Sponsor organisation

Celgene Corp.

Address

Route 206 And Province Line Road

City

Princeton

Postcode

08543-4000

Country

United States

Scientific contact point

Organisation

Celgene Corp.

Contact name

GSM-CT

Public contact point

Organisation

Celgene Corp.

Contact name

GSM-CT

Third parties 10

Locations

10 EU/EEA countries · 52 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 62 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

9 submissions — initial application plus substantial / non-substantial modifications