Safety study of oral azacitidine (CC-486) in patients with Acute Myeloid Leukemia or Myelodysplastic Syndromes experiencing no symptom of the disease after stem cell transplantation

• Register: EUCTR
• Last refreshed on: 21 August 2017
• Main ID: EUCTR2012-005805-36-GB
• Date of registration: 20/06/2013
• Prospective Registration: No
• Primary sponsor: Celgene Corporation
• Public title: Safety study of oral azacitidine (CC-486) in patients with Acute Myeloid Leukemia or Myelodysplastic Syndromes experiencing no symptom of the disease after stem cell transplantation
• Scientific title: A Phase 1/2, Dose and Schedule Finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Oral Azacitidine (CC-486) in Subjects with Acute Myeloid Leukemia or Myelodysplastic Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation - Quazar Post Transplant
• Date of first enrolment: 10/06/2013
• Target sample size: 30
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-005805-36
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: no Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

United Kingdom, United States

Contacts

• Name: ClinicalTrialDisclosure
• Affiliation: Celgene Corporation

• Name: ClinicalTrialDisclosure
• Affiliation: Celgene Corporation

Key inclusion & exclusion criteria

Inclusion criteria:
1. Age = 18 years at the time of signing the ICD
2. Diagnosis of MDS or AML according to WHO classification undergoing allogeneic HSCT using MAC, NMA or RIC preparative regimens (Bacigalupo, 2009), and with either peripheral blood or bone marrow as the source of hematopoietic stem cells
3. At the time of allogeneic HSCT:
• No prior allogeneic HSCT; and
• No more than 1 antigen mismatch at HLA-A, -B, -C, -DRB1 or -DQB1 locus for either related or unrelated donor; and
• Bone marrow blast < 20% if MDS or = 10% if AML; and
• Peripheral blood blast = 5%
4. Be able to start study therapy between 42 to 84 days following allogeneic HSCT
5. Post transplant bone marrow blast count = 5% confirmed within 21 days prior to starting study therapy
6. Adequate engraftment within 14 days prior to starting study therapy:
• ANC = 1.0 x 10*9/L without daily use of myeloid growth factor; and
• Platelet = 75 x 10*9/L without platelet transfusion within 1 week
7. Adequate organ function:
• Serum AST/SGOT and ALT/SGPT < 3 x upper limit of normal (ULN)
• Serum bilirubin < 2 x ULN. Higher levels are acceptable if these can be attributed to active RBC precursor destruction within the bone marrow (ie, ineffective erythropoiesis) or Gilbert’s syndrome
• Serum creatinine < 2 x ULN
8. Adequate coagulation (PT = 15 seconds, PTT = 40 seconds, and/or INR = 1.5)
9. ECOG performance status of 0, 1 or 2
10. Females of childbearing potential (FCBP) may participate, providing they meet the following conditions:
• Agree to use at least two effective contraceptive methods (oral, injectable,or
implantable hormonal contraceptive;tubal ligation;intra-uterine device;barrier
contraceptive with spermicide;or vasectomized partner) throughout the study, and for 3 months following the last dose of Investigational Product; and
• Have a negative serum pregnancy test (sensitivity of at least 25 mIU/mL) at screening; and
• Have a negative serum or urine (investigator’s discretion) pregnancy test (sensitivity of at least 25 mIU/mL) within 72 hours prior to starting study therapy in the treatment phase (note that the screening pregnancy test can be used as the test prior to starting study therapy in the treatment phase if it is performed within the 72-hour timeframe)
11. Male subjects with a female partner of childbearing potential must agree to the use of 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
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 27
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 3

Exclusion criteria:
1. Use of any of the following after transplantation and prior to starting study therapy:
• Chemotherapeutic agents for chemotherapy (note that prophylactic use of these agents is allowed in this study, eg, methotrexate for GVHD)
• Investigational agents/therapies
• Azacitidine, decitabine or other demethylating agents
• Lenalidomide, thalidomide and pomalidomide
2. Active GVHD grade II or higher
3. Any evidence of gastrointestinal (GI) GVHD
4. Concurrent use of corticosteroids equivalent of prednisone at a dose > 0.5 mg/kg
5. Known active viral infection with Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV)
6. Active 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)
7. Prior to allogeneic HSCT, history of inflammatory bowel disease (eg, Crohn’s disease, ulcerative colitis), celiac disease (ie, sprue), prior gastrectomy or upper bowel removal, or any other GI disorder or defect that may interfere with the absorption, distribution, metabolism or excretion of the Investigational Product and/or predispose the subject to an increased risk of gastrointestinal toxicity
8. Idiopathic thrombocytopenic purpura [ITP], disseminated intravascular coagulation, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura [TTP]
9. Prior history of malignancies, other than MDS or AML, unless the subject has been free of the disease for = 1 year. 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, node, metastasis [TNM] clinical staging system)
10. Significant active cardiac disease within the previous 6 months, including:
• New York Heart Association (NYHA) class III or IV congestive heart failure
• Unstable angina or angina requiring surgical or medical intervention; and/or
• Myocardial infarction
11. Known or suspected hypersensitivity to azacitidine or mannitol
12. Pregnant or lactating females
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. Any condition that confounds the ability to interpret data from the study


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Subjects with acute myeloid leukemia or myelodysplastic syndromes in morphological remission after allogeneic hematopoietic stem cell transplantation.
MedDRA version: 18.0 Level: LLT Classification code 10000887 Term: Acute myeloid leukemia in remission System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
MedDRA version: 18.0 Level: PT Classification code 10028533 Term: Myelodysplastic syndrome System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: Oral Azacitidine
Product Code: CC-486
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: AZACITIDINE
CAS Number: 320-67-2
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Product Name: Oral Azacitidine
Product Code: CC-486
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: AZACITIDINE
CAS Number: 320-67-2
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 150-

Product Name: Oral Azacitidine
Product Code: CC-486
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: AZACITIDINE
CAS Number: 320-67-2
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Primary Outcome(s)

Secondary Objective: 1) To determine the safety and tolerability of oral azacitidine in this subject population.
2) To assess the pharmacokinetics (PK) profile of oral azacitidine and to explore the relationships of azacitidine exposure with safety and efficacy endpoints.
3) To assess the preliminary efficacy of oral azacitidine in this subject population.

Main Objective: To determine the maximal tolerated dose (MTD) of oral azacitidine in subjects with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) after allogeneic hematopoietic stem cell transplantation (HSCT).

Primary end point(s): Maximum tolerated dose (MTD) of oral azacitidine in subjects with AML or MDS after allogeneic HSCT.

Timepoint(s) of evaluation of this end point: At the end of each cycle of Cycles 1 to 2

Secondary Outcome(s)

Timepoint(s) of evaluation of this end point: For Safety (which includes Time to discontinuation from treatment) and GVHD: on an ongoing basis;
For PK: several time points from Cycle 1 to Cycle 7;
For Efficacy (which involves Disease recurrence/relapse rate, Time to disease recurrence/relapse, Overall survival and relapse-free survival (RFS) at one year following allogeneic HSCT): every six months during the first year after transplantation

Secondary end point(s): - Safety (type, frequency, severity of AEs and relationship of AEs to oral azacitidine; progression to AML for MDS subjects)
- Incidence of acute and chronic graft-versus-host disease (GVHD)
- Time to discontinuation from treatment
- Plasma PK parameters including, but not limited to, area under the curve (AUC), half-life (t½), observed maximum concentration (Cmax), time at which maximum concentration is observed (tmax), and others as appropriate
- Disease recurrence/relapse rate
- Time to disease recurrence/relapse
- Overall survival and relapse-free survival (RFS) at one year following allogeneic HSCT.

Secondary ID(s)

CC-486-AML-002

Source(s) of Monetary Support

Celgene Corporation