NCT02281084

Safety and Efficacy Study of CC-486 in Subjects With Myelodysplastic Syndromes

Completed Phase 2 Results posted Last updated 4 October 2024

What this trial tests

Phase 2 trial testing Oral Azacitidine in Myelodysplastic Syndromes in 65 participants. Completed in 14 September 2023.

Timeline

6 July 2015

Primary endpoint
19 June 2019

14 September 2023

Quick facts

Lead sponsor	Celgene
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	65
Start date	6 July 2015
Primary completion	19 June 2019
Estimated completion	14 September 2023
Sites	89 locations across France, Italy, Belgium, United Kingdom, Germany, Poland, Canada, Australia

Drugs / interventions tested

• Oral Azacitidine
• Durvalumab — full drug profile →

Conditions studied

• Myelodysplastic Syndromes — all drugs for Myelodysplastic Syndromes →

Sponsor

Celgene — full company profile →

Who can join

18 and older, any sex, with Myelodysplastic Syndromes. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Overall Response Rate Based on the Modified International Working Group (IWG) 2006 Response Criteria for Myelodysplastic Syndrome (MDS) Primary · Response was assessed every 2 cycles following treatment during the first 6 cycles, then every 3 cycles thereafter; median duration of treatment = 5.26 and 3.81 months for SD/PD for oral AZA arms respectively, and 1.84 months for AZA and Durva SD/PD arms

The overall response rate (ORR) was defined as the percentage of participants who achieved an objective response including: hematologic improvement (HI), partial remission (PR), complete remission (CR), or marrow complete remission (mCR). Hematologic response was defined as: • CR: ≤ 5% myeloblasts with normal maturation of all cell lines; peripheral blood (PB) shows: hemoglobin ≥11 g/dL, neutrophils ≥1.0x10\^9/L, platelets ≥100x10\^9/dL, blasts (0%) • PR: same as CR bone marrow (BM) shows blasts decreased by ≥ 50% over pre-treatment but still \> 5%; cellularity and morphology not relevant • mC

Group	Value	95% CI
Stable Disease (SD) Cohort: Oral Azacitidine	6.3	0.8 – 20.8
Progressive Disease (PD) Cohort: Oral Azacitidine	4.5	0.1 – 22.8
Stable Disease Cohort: Oral Azacitidine and Durvalumab	16.7	0.4 – 64.1
Progressive Disease Cohort: Oral Azacitidine and Durvalumab	0	NA – NA

Kaplan-Meier Estimate of Overall Survival Secondary · From first dose till death due to any cause (Up to 91 months)

Overall survival (OS) was defined as the time from randomization to death from any cause, and was calculated using date of first dose and date of death, or date of last follow-up for censored subjects.

Group	Value	95% CI
Stable Disease (SD) Cohort: Oral Azacitidine	17.00	10.03 – 24.99
Progressive Disease (PD) Cohort: Oral Azacitidine	6.28	4.50 – 15.19
Stable Disease Cohort: Oral Azacitidine and Durvalumab	14.70	1.58 – NA
Progressive Disease Cohort: Oral Azacitidine and Durvalumab	14.56	9.73 – NA

Kaplan Meier Estimate of Time to Onset of First and Best Response Secondary · Response was assessed every 2 cycles following treatment during the first 6 cycles, then every 3 cycles thereafter; median duration of treatment = 5.26 and 3.81 months for SD/PD for oral AZA arms respectively, and 1.84 months for AZA and Durva SD/PD arms

Time to onset of first response was defined as the time between the date of first investigational product (IP) dose and the earliest date any response (CR, PR, mCR, or HI) was first observed. Participants who did not achieve any defined response during the treatment period were censored at the date of treatment discontinuation, disease progression, or death, whichever occurred first. Best response is the best recorded response or treatment outcome from the start of the study treatment until the end of the study treatment taking into account the requirements for confirmation of response.

Onset of First Response

Group	Value	95% CI
Stable Disease (SD) Cohort: Oral Azacitidine	NA	10.85 – NA
Progressive Disease (PD) Cohort: Oral Azacitidine	11.97	NA – NA
Stable Disease Cohort: Oral Azacitidine and Durvalumab	NA	1.64 – NA
Progressive Disease Cohort: Oral Azacitidine and Durvalumab	NA	NA – NA

Onset of Best Response

Group	Value	95% CI
Stable Disease (SD) Cohort: Oral Azacitidine	3.68	2.10 – NA
Progressive Disease (PD) Cohort: Oral Azacitidine	4.41	1.68 – NA
Stable Disease Cohort: Oral Azacitidine and Durvalumab	3.29	1.64 – NA
Progressive Disease Cohort: Oral Azacitidine and Durvalumab	2.17	1.64 – NA

Kaplan Meier Estimate of Duration of First Response Secondary · Response was assessed every 2 cycles following treatment during the first 6 cycles, then every 3 cycles thereafter; median duration of treatment = 5.26 and 3.81 months for SD/PD for oral AZA arms respectively, and 1.84 months for AZA and Durva SD/PD arms

Duration of hematologic response and/or improvement was defined as the time from the date response or improvement was first observed to the date of documented relapse or disease progression as defined by the modified IWG 2006 criteria. Particpants who maintained hematologic response and/or improvement through the end of the treatment period were censored as the date of treatment discontinuation or death, whichever occurred first.

Group	Value	95% CI
Stable Disease (SD) Cohort: Oral Azacitidine	NA	9.24 – NA
Progressive Disease (PD) Cohort: Oral Azacitidine	NA	NA – NA
Stable Disease Cohort: Oral Azacitidine and Durvalumab	NA	NA – NA

Kaplan Meier Estimate of Duration of Best Response Secondary · Response was assessed every 2 cycles following treatment during the first 6 cycles, then every 3 cycles thereafter; median duration of treatment = 5.26 and 3.81 months for SD/PD for oral AZA arms respectively, and 1.84 months for AZA and Durva SD/PD arms

Duration of hematologic response and/or improvement was defined as the time from the date response or improvement was first observed to the date of documented relapse or disease progression as defined by the modified IWG 2006 criteria. Particpants who maintained hematologic response and/or improvement through the end of the treatment period were censored as the date of treatment discontinuation or death, whichever occurred first.

Group	Value	95% CI
Stable Disease (SD) Cohort: Oral Azacitidine	NA	9.24 – NA
Progressive Disease (PD) Cohort: Oral Azacitidine	NA	NA – NA
Stable Disease Cohort: Oral Azacitidine and Durvalumab	NA	NA – NA
Progressive Disease Cohort: Oral Azacitidine and Durvalumab	NA	NA – NA

Kaplan-Meier Estimate of Progression Free Survival (PFS) Secondary · From first dose to the first documented progressive disease (PD), relapse, or death due to any cause (Up to 91 months)

Progression-free survival is defined as the time from first dose to the first documented progressive disease (PD), relapse, or death due to any cause during or after the treatment period, whichever occurred first, according to IWG 2006 response criteria for MDS. Participants who were still alive and progression-free were censored at the date of their last response assessment. Progressive disease is defined as follows: - an increase in BM blasts relative to nadir: •If nadir less than 5% blasts: ≥ 50% increase in blasts to \> 5% blasts •If nadir 5% - 10% blasts: ≥ 50% increase in blasts to \> 10

Group	Value	95% CI
Stable Disease (SD) Cohort: Oral Azacitidine	14.86	9.27 – 24.99
Progressive Disease (PD) Cohort: Oral Azacitidine	6.28	4.50 – 15.19
Stable Disease Cohort: Oral Azacitidine and Durvalumab	14.70	1.58 – NA
Progressive Disease Cohort: Oral Azacitidine and Durvalumab	12.10	2.17 – NA

Percentage of Participants With Progressive Disease at Baseline Who Achieved Stable Disease Secondary · Response was assessed every 2 cycles following treatment during the first 6 cycles, then every 3 cycles thereafter; median duration of treatment = 5.26 and 3.81 months for SD/PD for oral AZA arms respectively, and 1.84 months for AZA and Durva SD/PD arms

A participant was considered as having a stable disease if the disease neither responded nor progressed during or after study treatment.

Group	Value	95% CI
Progressive Disease (PD) Cohort: Oral Azacitidine	36.4
Progressive Disease Cohort: Oral Azacitidine and Durvalumab	20.0

Kaplan-Meier Estimate of Onset to Achieve Stable Disease Secondary · Response was assessed every 2 cycles following treatment during the first 6 cycles, then every 3 cycles thereafter; median duration of treatment = 5.26 and 3.81 months for SD/PD for oral AZA arms respectively, and 1.84 months for AZA and Durva SD/PD arms

A participant was considered as having a stable disease if the disease neither responded nor progressed during or after study treatment.

Group	Value	95% CI
Progressive Disease (PD) Cohort: Oral Azacitidine	NA	1.74 – NA
Progressive Disease Cohort: Oral Azacitidine and Durvalumab	NA	1.64 – NA

Kaplan-Meier Estimate of Duration of Stable Disease Secondary · Response was assessed every 2 cycles following treatment during the first 6 cycles, then every 3 cycles thereafter; median duration of treatment = 5.26 and 3.81 months for SD/PD for oral AZA arms respectively, and 1.84 months for AZA and Durva SD/PD arms

The duration of stable disease was defined as the time between any two observations of objective disease progression (modified IWG criteria), starting from the first day of dosing with IP. Participants who maintained stable disease through the end of the treatment period were censored at the date of study termination.

Group	Value	95% CI
Stable Disease (SD) Cohort: Oral Azacitidine	NA	10.85 – NA
Progressive Disease (PD) Cohort: Oral Azacitidine	NA	10.16 – NA
Progressive Disease Cohort: Oral Azacitidine and Durvalumab	NA	NA – NA

Percentage of Participants Who Progressed to Acute Myelogenous Leukemia (AML) Secondary · From first dose and until death, loss to follow-up, withdrawal of consent for further data collection (Up to 91 months)

For all participants who received at least one dose of study drug, continuous monitoring for progression to AML occurred in the post treatment follow up period.

Group	Value	95% CI
Stable Disease (SD) Cohort: Oral Azacitidine	31.3
Progressive Disease (PD) Cohort: Oral Azacitidine	18.2
Stable Disease Cohort: Oral Azacitidine and Durvalumab	33.3
Progressive Disease Cohort: Oral Azacitidine and Durvalumab	60.0

Kaplan-Meier Estimate of Time to Progression to AML Secondary · From first dose and until death, loss to follow-up, withdrawal of consent for further data collection (Up to 91 months)

Time to AML progression was defined as the time from the date of first dose of IP until the date the participant had documented progression to AML.

Group	Value	95% CI
Stable Disease (SD) Cohort: Oral Azacitidine	NA	12.89 – NA
Progressive Disease (PD) Cohort: Oral Azacitidine	NA	8.42 – NA
Stable Disease Cohort: Oral Azacitidine and Durvalumab	21.47	1.68 – NA
Progressive Disease Cohort: Oral Azacitidine and Durvalumab	6.21	1.64 – NA

Number of Participants With Treatment Emergent Adverse Events (TEAEs) Secondary · From first dose until 28 days after the last dose of CC-486 (90 days after the last dose of durvalumab) or the last follow up visit, whichever date is later (Up to 91 months)

TEAEs were defined as AEs occurring or worsening on or after the date of the first dose of oral aza or durva and within 28 days after last dose of oral aza or 90 days after last dose of durva A serious adverse event (SAE) is any: • Death; • Life-threatening event; • Any inpatient hospitalization or prolongation of existing hospitalization; • Persistent or significant disability or incapacity; • Congenital anomaly or birth defect; • Any other important medical event The severity of an AE was evaluated by the investigator according to National Cancer Institute Common Terminology Criteria for Adv

≥ 1 TEAE

Group	Value	95% CI
Stable Disease (SD) Cohort: Oral Azacitidine	32
Progressive Disease (PD) Cohort: Oral Azacitidine	22
Stable Disease Cohort: Oral Azacitidine and Durvalumab	6
Progressive Disease Cohort: Oral Azacitidine and Durvalumab	5

≥ 1 TEAE Related to (R/T) Oral Azacitidine (AZA)

Group	Value	95% CI
Stable Disease (SD) Cohort: Oral Azacitidine	28
Progressive Disease (PD) Cohort: Oral Azacitidine	20
Stable Disease Cohort: Oral Azacitidine and Durvalumab	6
Progressive Disease Cohort: Oral Azacitidine and Durvalumab	4

≥ 1 TEAE R/T Durvalumab (Durva)

Group	Value	95% CI
Stable Disease (SD) Cohort: Oral Azacitidine	0
Progressive Disease (PD) Cohort: Oral Azacitidine	0
Stable Disease Cohort: Oral Azacitidine and Durvalumab	5
Progressive Disease Cohort: Oral Azacitidine and Durvalumab	4

≥ 1 TEAE R/T Oral AZA or Durva

Group	Value	95% CI
Stable Disease (SD) Cohort: Oral Azacitidine	28
Progressive Disease (PD) Cohort: Oral Azacitidine	20
Stable Disease Cohort: Oral Azacitidine and Durvalumab	6
Progressive Disease Cohort: Oral Azacitidine and Durvalumab	4

≥ 1 Serious TEAE

Group	Value	95% CI
Stable Disease (SD) Cohort: Oral Azacitidine	25
Progressive Disease (PD) Cohort: Oral Azacitidine	15
Stable Disease Cohort: Oral Azacitidine and Durvalumab	4
Progressive Disease Cohort: Oral Azacitidine and Durvalumab	5

≥ 1 Serious TEAE R/T Oral AZA

Group	Value	95% CI
Stable Disease (SD) Cohort: Oral Azacitidine	4
Progressive Disease (PD) Cohort: Oral Azacitidine	3
Stable Disease Cohort: Oral Azacitidine and Durvalumab	2
Progressive Disease Cohort: Oral Azacitidine and Durvalumab	1

≥ 1 Serious TEAE R/T Durva

Group	Value	95% CI
Stable Disease (SD) Cohort: Oral Azacitidine	0
Progressive Disease (PD) Cohort: Oral Azacitidine	0
Stable Disease Cohort: Oral Azacitidine and Durvalumab	1
Progressive Disease Cohort: Oral Azacitidine and Durvalumab	1

≥ 1 Serious TEAE R/T Oral AZA or Durva

Group	Value	95% CI
Stable Disease (SD) Cohort: Oral Azacitidine	4
Progressive Disease (PD) Cohort: Oral Azacitidine	3
Stable Disease Cohort: Oral Azacitidine and Durvalumab	2
Progressive Disease Cohort: Oral Azacitidine and Durvalumab	1

Adverse events — posted to ClinicalTrials.gov

Time frame: SAE and Non-SAEs were collected from first dose until 28 days after the last dose of CC-486 (90 days after the last dose of durvalumab) or the last follow up visit, whichever date is later (Up to 91 months). Participants were assessed for all-cause mortality from first dose till death due to any cause (Up to 91 months).. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Stable Disease (SD) Cohort: Oral Azacitidine

Serious: 25/32 (78%)

Deaths: 22/32

Progressive Disease (PD) Cohort: Oral Azacitidine

Serious: 15/22 (68%)

Deaths: 18/22

Stable Disease Cohort: Oral Azacitidine and Durvalumab

Serious: 4/6 (67%)

Deaths: 3/6

Progressive Disease Cohort: Oral Azacitidine and Durvalumab

Serious: 5/5 (100%)

Deaths: 5/5

Serious adverse events (68 terms)

Reaction	System	Stable Disease (SD) Cohort…	Progressive Disease (PD) C…	Stable Disease Cohort: Ora…	Progressive Disease Cohort…
Pneumonia	Infections and infestations	—	—	—	—
Transformation to acute myeloid leukaemia	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—
Sepsis	Infections and infestations	—	—	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—	—	—
Pyrexia	General disorders	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—
Hyperleukocytosis	Blood and lymphatic system disorders	—	—	—	—
Leukocytosis	Blood and lymphatic system disorders	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—
Myocardial infarction	Cardiac disorders	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—
Haematemesis	Gastrointestinal disorders	—	—	—	—
Intestinal ischaemia	Gastrointestinal disorders	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—
Rectal haemorrhage	Gastrointestinal disorders	—	—	—	—
Death	General disorders	—	—	—	—
General physical health deterioration	General disorders	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—
Autoimmune hepatitis	Hepatobiliary disorders	—	—	—	—
Hepatitis	Hepatobiliary disorders	—	—	—	—
Appendicitis	Infections and infestations	—	—	—	—
Arthritis infective	Infections and infestations	—	—	—	—
Bacteraemia	Infections and infestations	—	—	—	—

Other adverse events (136 terms — click to expand)

Reaction	System	Stable Disease (SD) Cohort…	Progressive Disease (PD) C…	Stable Disease Cohort: Ora…	Progressive Disease Cohort…
Nausea	Gastrointestinal disorders	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—
Decreased appetite	Metabolism and nutrition disorders	—	—	—	—
Constipation	Gastrointestinal disorders	—	—	—	—
Anaemia	Blood and lymphatic system disorders	—	—	—	—
Neutropenia	Blood and lymphatic system disorders	—	—	—	—
Fatigue	General disorders	—	—	—	—
Weight decreased	Investigations	—	—	—	—
Asthenia	General disorders	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Thrombocytopenia	Blood and lymphatic system disorders	—	—	—	—
Pyrexia	General disorders	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—
Insomnia	Psychiatric disorders	—	—	—	—
Oral herpes	Infections and infestations	—	—	—	—
Contusion	Injury, poisoning and procedural complications	—	—	—	—
Fall	Injury, poisoning and procedural complications	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—	—	—
Stomatitis	Gastrointestinal disorders	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—
Hypokalaemia	Metabolism and nutrition disorders	—	—	—	—
Muscular weakness	Musculoskeletal and connective tissue disorders	—	—	—	—
Headache	Nervous system disorders	—	—	—	—
Febrile neutropenia	Blood and lymphatic system disorders	—	—	—	—
Abdominal distension	Gastrointestinal disorders	—	—	—	—
Abdominal pain	Gastrointestinal disorders	—	—	—	—
Abdominal pain upper	Gastrointestinal disorders	—	—	—	—
Dyspepsia	Gastrointestinal disorders	—	—	—	—
Flatulence	Gastrointestinal disorders	—	—	—	—
Folliculitis	Infections and infestations	—	—	—	—
Oral candidiasis	Infections and infestations	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—
Blood creatinine increased	Investigations	—	—	—	—

Most-reported serious reactions: Pneumonia, Transformation to acute myeloid leukaemia, Sepsis, Febrile neutropenia, Pyrexia, Back pain, Hyperleukocytosis, Leukocytosis.

Data from ClinicalTrials.gov NCT02281084 adverse events section.

Sponsor's own description

Evaluate the safety and efficacy of oral azacitidne (CC-486) twice daily (BID) in subjects with myelodysplastic syndromes who failed to achieve an objective response post injectable hypomethylating agent (iHMA) treatment

Reason for removing the combination arm: Due to difficulties with dose-finding, the durvalumab plus CC-486 combination arm was closed to enrollment.

Extension:

An Extension Phase (EP) has been added to allow subjects who are currently receiving oral azacitidine BID and who are demonstrating clinical benefit as assessed by the Investigator, to continue receiving oral azacitidine until the subject meets the criteria for study discontinuation.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Immune checkpoint therapy in liver cancer.
   Xu F, Jin T, Zhu Y, Dai C. · · 2018 · cited 299× · PMID 29843754 · DOI 10.1186/s13046-018-0777-4
2. Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets.
   Yang J, Xu J, Wang W, Zhang B, et al · · 2023 · cited 251× · PMID 37217462 · DOI 10.1038/s41392-023-01480-x
3. Checkpoint inhibitors in hematological malignancies.
   Ok CY, Young KH. · · 2017 · cited 93× · PMID 28482851 · DOI 10.1186/s13045-017-0474-3
4. The double-edged sword of (re)expression of genes by hypomethylating agents: from viral mimicry to exploitation as priming agents for targeted immune checkpoint modulation.
   Wolff F, Leisch M, Greil R, Risch A, et al · · 2017 · cited 68× · PMID 28359286 · DOI 10.1186/s12964-017-0168-z
5. Epigenetics in Cancer: A Hematological Perspective.
   Stahl M, Kohrman N, Gore SD, Kim TK, et al · · 2016 · cited 67× · PMID 27723796 · DOI 10.1371/journal.pgen.1006193
6. Targeting PD-1/PD-L1 pathway in myelodysplastic syndromes and acute myeloid leukemia.
   Yang X, Ma L, Zhang X, Huang L, et al · · 2022 · cited 63× · PMID 35236415 · DOI 10.1186/s40164-022-00263-4
7. Immune checkpoint blockade for hematologic malignancies: a review.
   Pianko MJ, Liu Y, Bagchi S, Lesokhin AM. · · 2017 · cited 48× · PMID 28529947 · DOI 10.21037/sci.2017.03.04
8. The epigenetic hallmarks of immune cells in cancer.
   Ji Y, Xiao C, Fan T, Deng Z, et al · · 2025 · cited 28× · PMID 40038722 · DOI 10.1186/s12943-025-02255-4