Leukemia, Myeloid, AcutePhase 1/2NCT01835587
Safety Study of Oral Azacitidine (CC-486) as Maintenance Therapy After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Participants With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS).
A Phase 1/2 study testing CC-486 in people with Leukemia, Myeloid, Acute and Myelodysplastic Syndromes, run by Celgene at 5 sites in 2 countries.
Trial summary
The purpose of the study is to determine the maximal tolerated dose and schedule of CC-486, known as oral azacitidine, in patients with AML or MDS after allogeneic hematopoetic stem cell transplant (HSCT). HSCT is more frequently used in AML or MDS as a potential curative therapy. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Leukemia, Myeloid, Acute, Myelodysplastic Syndromes
- What is being tested?
- CC-486
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 31 participants
- Where
- 5 sitesin 2 countries
- Study dates
- 25 Oct 2013to 26 May 2017
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically confirmed Myelodysplastic Syndromes or Acute Myeloid Leukemia undergoing allogeneic hematopoietic stem cell transplantation with either peripheral blood or bone marrow as the source of hematopoietic stem cells
- At the time of allogeneic HSCT:
- No prior allogeneic HSCT; and
- No more than 1 antigen mismatch at Human Leukocyte Antigen (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%
Show all 19Show fewer
- Be able to start study drug between 42 to 84 days following allogeneic HSCT
- Post transplant bone marrow blast count ≤ 5% confirmed within 21 days prior to starting study therapy
- Adequate engraftment within 14 days prior to starting study therapy:
- Absolute Neutrophil count (ANC) ≥ 1.0 x 10^9/L without daily use of myeloid growth factor; and
- Platelet count 75 x 10^9/L without platelet transfusion within one week.
- Adequate organ function:
- Serum aspartate transaminase (AST) and alanine transaminase (ALT) < 3 x upper limit of normal (ULN)
- Serum bilirubin < 2 x ULN
- Serum creatinine < 2 x ULN
- Adequate coagulation (Prothrombin time [PT] ≤ 15 seconds, Partial thromboplastin time (PTT) ≤ 40 seconds, and/or International normalized ratio [INR] ≤ 1.5)
- Have a negative serum pregnancy test (sensitivity of at least 25 mIU/mL at screening).
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
- Must agree to follow protocol-specified pregnancy precautions
Who cannot join
- Use of any of the following after transplantation and prior to starting oral azacitidine:
- Chemotherapeutic agents for chemotherapy
- Investigational agents/therapies
- Azacitidine, decitabine or other demethylating agents
- Lenalidomide, thalidomide and pomalidomide
- Active Graft-versus-host disease (GVHD) grade II or higher
Show all 12Show fewer
- Any evidence of gastrointestinal (GI) GVHD
- Concurrent use of corticosteroids equivalent of prednisone at a dose > 0.5 mg/kg
- Known active viral infection with Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV)
- Active uncontrolled systemic fungal, bacterial or viral infection
- Presence of malignancies, other than MDS or AML, within the previous 12 months
- Significant active cardiac disease within the previous 6 months
Trial locations and contacts
5 sites in 2 countries.
5 sites in 2 countries
United States4 sites
University Hospitals Cleveland Medical Center
Cleveland, Ohio, 44106
MD Anderson Cancer Center The University of Texas
Houston, Texas, 77030
Memorial Sloan-Kettering Cancer Center.
New York, New York, 10065
Fred Hutchinson Cancer Research Center
Seattle, Washington, 98109-4417
United Kingdom1 site
Queen Elizabeth Hospital UHB NHS Foundation Trust
Birmingham, B15 2TH
About this study
Official 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 Myelogenous Leukemia and Myelodysplastic Syndromes After Allogeneic Hematopoietic Stem Cell Transplantation
The purpose of the study is to determine the maximal tolerated dose and schedule of CC-486, known as oral azacitidine, in patients with AML or MDS after allogeneic hematopoetic stem cell transplant (HSCT). HSCT is more frequently used in AML or MDS as a potential curative therapy. However, disease recurrence/relapse and graft-versus-host disease (GVHD) remain the principal causes of fatal complications after transplantation. Oral azacitidine has significant activity in MDS and AML. Oral azacitidine has also demonstrated immunomodulatory activity in AML patients after allogeneic HSCT. An oral formulation of oral azacitidine provides a convenient route of administration and an opportunity to deliver the drug over a prolonged schedule.
Read the detailed description
This is an open-label, multicenter study of oral azacitidine in MDS or AML patients who have undergone allogeneic HSCT. The study consists of three phases: Screening, Treatment and Follow-up. During the Screening phase, the study doctor will do tests to see if the patient is suitable for this study. The patients meeting protocol-specified entry criteria will enter the treatment phase and be assigned to receive one of the oral azacitidine cohorts. The dosing group of 200 mg QD on Days 1 to 7 will be evaluated first (ie, Cohort 1). In the event that unacceptable toxicity occurs in Cohort 1, then oral azacitidine may be evaluated at lower dose levels (eg, 150 mg). If the dosing regimen is confirmed to be safe in Cohort 1, other cohorts will be evaluated sequentially. During the treatment phase, patients will be monitored closely for safety and tolerability. Dosing interruption or delay, dose or schedule reduction, intra-subject dose/schedule escalation or re-escalation may occur on the basis of protocol-specified dosing adjustment guidelines. Safety will be monitored throughout the study at predetermined intervals and as clinically indicated by vital signs, physical examination, performance status, laboratory tests and evaluation of adverse events. The patient can continue to receive the study treatment for up to 12 months provided that they benefit from the study treatment and all protocol-specified criteria are met. However, the patient may receive the study treatment for less than 12 months due to adverse event, disease recurrence or progression. When the study treatment is discontinued, all patients who have received at least one dose of oral azacitidine will be asked to see the study doctor for the treatment discontinuation visit. Thereafter, all patients discontinued from the study treatment will enter the Follow-up phase for safety and survival follow up.
- Being tested
- CC-486
- Keywords
- Acute myeloid leukemia,, myelodysplastic syndromes,, CC-486, oral Azacitidine,, transplantation,, allogeneic,, HSCT.
- Medical subject headings
- Leukemia, Myeloid, Acute, Myelodysplastic Syndromes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CC-486Drug
Also called Oral Azacitdine
Cohorts of 3 to 6 subjects will be treated at escalating or de-escalating sequential dose levels until a preliminary Maximum Tolerated Dose (MTD) is identified.
| Study group | Role | What they receive |
|---|---|---|
| CC-486 | Experimental | Dose of 150 mg, 200 mg, or 300 mg once daily (QD) for the first 7, 10, or 14 days of each 28-day cycle, starting 42-84 days after transplantation. Receives: Drug: CC-486 |
What is being measured
The primary outcome is the main question the study is designed to answer.
The Number of Participants With Dose Limiting Toxicities (DLT)
A DLT included events that started within 28 days of the first dose of CC-486 in a 28-day cycle, constituted a change from baseline irrespective of outcome, as decided by the investigator to be related to CC-486 including:
- ≥ Grade (GR) 3 nausea, diarrhea, or vomiting despite the use of medical support
- Other significant nonhematologic toxicity of ≥ GR 3 considered not related to the disease or intercurrent illness • Absolute neutrophil count (ANC) < 0.5 x 10^9/L for > 1 week despite growth factor support
- Platelets < 25 x 10^9/L for > 1 week despite transfusion support
- Failure of recovery to an ANC ≥ 1.0 x 10^9/L and/or platelets ≥ 50 x 10^9/L with a hypocellular marrow by 56 days after the start of a cycle of CC-486 not due to relapse or progressive disease.
The maximum tolerated dose is defined as the cohort delivering the highest dose in which no more than 33% of the evaluable subjects had a DLT The safety population included subjects who received ≥ 1 dose of CC-486
Measured: 2 months (Cycles 1 and 2)
Number of Participants With Treatment Emergent Adverse Events (TEAE)
A TEAE was defined as any AE with an onset date on or after the first dose of IP or any event already present that worsened in severity or increased in frequency after exposure to IP up to 28 days after the last dose. In addition, an AE that occurred beyond the timeframe and was assessed by the doctor as possibly related to IP was considered to be treatment-emergent. Severity was assessed using National Cancer Institute Common Toxicity Terminology Criteria for AEs (NCI CTCAE) version 4.0, where 1= Mild; 2= Moderate; 3= Severe; 4= Life-threatening; 5= Death related to AE. Serious AEs resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in a medical event that may have jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes above.
Measured: From the first dose of investigational product (IP) up to 28 days after the last dose of IP. The median duration of exposure was 252.5 days overall; up to the final data cut off date of 14 July 2017
Secondary outcomes (13)
Percentage of Participants With Graft Versus Host Disease During the Entire Course of the Study
Acute graft versus host disease generally occurs after allogeneic hematopoietic stem cell transplantation. It is a reaction of donor immune cells against host tissues. The 3 main tissues that acute GVHD affects are the skin, liver, and gastrointestinal tract. Chronic GVHD is scored per the National Institute of Health consensus conference grading system. Clinical manifestations of chronic GVHD include skin involvement resembling lichen planus or the cutaneous manifestations of scleroderma; dry oral mucosa with ulcerations and sclerosis of the gastrointestinal tract; and a rising serum bilirubin concentration.
Measured: From the first dose of CC-486 up to study discontinuation or death. Up to final data cut off date of 14 July 2017; up to 186 weeks and 4 days
Kaplan Meier Estimate of Time to Discontinuation From Treatment
The time to discontinuation from treatment was assessed as an estimate of treatment tolerability and was defined as the interval from the date of the first IP dose to the date of discontinuation from IP as indicated on the discontinuation from treatment Case Report Form page. Time to discontinuation from study treatment was analyzed using the Kaplan-Meier method where participants who did not discontinue were censored at the date of last visit.
Measured: From the first dose of IP dose to the date of discontinuation from IP; the overall median time to discontinuation of IP was 283.5 days
Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration Of CC-486 (AUC-t)
Area under the plasma concentration-time curve from Time 0 to the time of the last quantifiable concentration, calculated by linear trapezoidal method when concentrations are increasing and the logarithmic trapezoidal method when concentrations are decreasing.
Measured: On Day 1, pharmacokinetic (PK) samples were collected at predose and over a 6-hour period following drug administration on the following schedule: 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours post-dose; Cycle 1 or 2 until 6 hours after CC-486 administration.
Area Under the Plasma Concentration-Time Curve From Time 0 to Extrapolated to Infinity (AUC-inf; AUC0-∞) Of CC-486
Area under the plasma concentration-time curve from time 0 extrapolated to infinity, calculated as [AUCt + Ct/ λz]. Ct is the last quantifiable concentration. No AUC extrapolation was performed with unreliable λz. If AUC %Extrap was ≥25%, AUC inf was not reported.
Measured: On Day 1, PK samples were collected at predose and over the 6-hour period following CC-486 administration on the following schedule: 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours post-dose at Cycle 1 or 2 until 6 hours after CC-486 administration.
Maximum Observed Concentration (Cmax) Of CC-486
Maximum observed plasma concentration, obtained directly from the observed concentration versus time data.
Measured: On Day 1, PK samples were collected at predose and over the 6-hour period following CC-486 administration on the following schedule: 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours post-dose at Cycle 1 or 2 until 6 hours after CC-486 administration.
Time to Reach Maximum Concentration (Tmax) of CC-486
Time to Cmax, obtained directly from the observed concentration versus time data.
Measured: On Day 1, PK samples were collected at predose and over the 6-hour period following CC-486 administration on the following schedule: 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours post-dose at Cycle 1 or 2 until 6 hours after CC-486 administration.
Terminal Half-Life (T1/2) of CC-486
Terminal phase half-life in plasma, calculated as [(ln 2)/λz]. t1/2 will only be calculated when a reliable estimate for λz can be obtained.
Measured: On Day 1, PK samples were collected at predose and over the 6-hour period following CC-486 administration on the following schedule: 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours post-dose at Cycle 1 or 2 until 6 hours after CC-486 administration.
Apparent Total Clearance (CL/F) of CC-486
Apparent total clearance, calculated as [Dose/AUCinf].
Measured: On Day 1, PK samples were collected at predose and over the 6-hour period following CC-486 administration on the following schedule: 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours post-dose at Cycle 1 or 2 until 6 hours after CC-486 administration.
Apparent Volume of Distribution (Vz/F) of CC-486
Apparent volume of distribution, calculated as [(CL/F)/λz].Apparent volume of distribution, calculated as [(CL/F)/λz].
Measured: On Day 1, PK samples were collected at predose and over the 6-hour period following CC-486 administration on the following schedule: 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours post-dose at Cycle 1 or 2 until 6 hours after CC-486 administration.
Percentage of Participants With Disease Relapse or Progression
Disease relapse was defined as the reappearance of > 5% blasts in the bone marrow that persists for at least 4 weeks. Disease progression was defined as the reappearance of > 10% of blasts in the bone marrow that persisted for at least 4 weeks.
Measured: Date of first dose of IP to disease relapse or progression; up to data cut-off date of 14 July 2017; median number of days assessed was 963.0 days for Cohort 1, 743.5 days for Cohort 2, 675.5 days for Cohort 3A and 559.0 days for Cohort 3.
Time to Disease Recurrence/Progression
Time to disease relapse/progression was defined as the interval from the date of allogeneic HSCT to the date of treatment discontinuation or study discontinuation where reason for discontinuation is disease relapse or disease progression, or the date of disease progression recorded on the survival electronic Case Report Form page, whichever occurred first. Time to disease relapse/progression was analyzed using competing risk methods where death without documented relapse/progression was treated as a competing risk for relapse/progression. relapse/progression.
Measured: Date of allogenic HSCT to disease progression or relaopse; up to data cut-off date of 14 July 2017; median number of days assessed was 963.0 days for Cohort 1, 743.5 days for Cohort 2, 675.5 days for Cohort 3A and 559.0 days for Cohort 3.
Overall Survival
Overall Survival was defined as the time from the date of allogeneic hematopoietic stem cell transplantation to death from any cause.
Measured: Date of the allogeneic HSCT to death from any cause. Median number of days participants were assessed from first dose to last contact was 963.0 days for Cohort 1, 743.5 days for Cohort 2, 675.5 days for Cohort 3A and 559.0 days for Cohort 3.
Kaplan Meier Estimate of Relapse-Free Survival (RFS)
Relapse-free survival was defined as the interval from the date of allogeneic HSCT to the date of first documented > 5% blasts in the bone marrow or death from any cause, whichever occurs first. Participants who were still alive and continued to have less than or equal to 5% blasts in the bone marrow or who were lost to follow-up were censored at the date of their last response assessment.
Measured: Date of allogenic HSCT to date of progression or death from any cause; Median number of days participants were assessed from first dose to last contact was 963 days for Cohort 1, 674.8 days for Cohort 2, 577.5 days for Cohort 3A and 553 days for Cohort 3
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Apr 2013 (estimated)
- Study start25 Oct 2013
- Primary completion13 Nov 2016
- Study completion26 May 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Leukemia, Myeloid, AcuteStudies of the same condition, open and under way.
- More trials run by CelgeneThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 31 participants (actual)
Sponsor and investigators
- Lead sponsor
- Celgene
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Barry Skikne, M.D., FACP; FCP (SA), Study director, Celgene Corporation
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01835587
- Sponsor's protocol ID
- CC-486-AML-002
- Status last verified
- Oct 2018
- First submitted
- 17 Apr 2013
- Last updated
- 20 Nov 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
de Lima M, Oran B, Champlin RE, Papadopoulos EB, Giralt SA, Scott BL, William BM, Hetzer J, Laille E, Hubbell B, Skikne BS, Craddock C. CC-486 Maintenance after Stem Cell Transplantation in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndromes. Biol Blood Marrow Transplant. 2018 Oct;24(10):2017-2024. doi: 10.1016/j.bbmt.2018.06.016. Epub 2018 Jun 20.
PubMed 29933073
Study at a glance
From the registry record, last updated by the sponsor on 20 Nov 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official 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 Myelogenous Leukemia and Myelodysplastic Syndromes After Allogeneic Hematopoietic Stem Cell Transplantation
- ClinicalTrials.gov ID
- NCT01835587
- Acronym / sponsor ID
- CC-486-AML-002
- Keywords
- Acute myeloid leukemia,, myelodysplastic syndromes,, CC-486, oral Azacitidine,, transplantation,, allogeneic,, HSCT.
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 31 participants (actual)
- Lead sponsor
- CelgeneIndustry (pharma, biotech, devices)
- Study start
- 25 Oct 2013 (actual)
- Primary completion
- 13 Nov 2016 (actual)
- Study completion
- 26 May 2017 (actual)
- First posted
- 19 Apr 2013 (estimated)
- Results
- Posted 20 Nov 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of the study is to determine the maximal tolerated dose and schedule of CC-486, known as oral azacitidine, in patients with AML or MDS after allogeneic hematopoetic stem cell transplant (HSCT). HSCT is more frequently used in AML or MDS as a potential curative therapy. However, disease recurrence/relapse and graft-versus-host disease (GVHD) remain the principal causes of fatal complications after transplantation. Oral azacitidine has significant activity in MDS and AML. Oral azacitidine has also demonstrated immunomodulatory activity in AML patients after allogeneic HSCT. An oral formulation of oral azacitidine provides a convenient route of administration and an opportunity to deliver the drug over a prolonged schedule.
Detailed description
This is an open-label, multicenter study of oral azacitidine in MDS or AML patients who have undergone allogeneic HSCT. The study consists of three phases: Screening, Treatment and Follow-up. During the Screening phase, the study doctor will do tests to see if the patient is suitable for this study. The patients meeting protocol-specified entry criteria will enter the treatment phase and be assigned to receive one of the oral azacitidine cohorts. The dosing group of 200 mg QD on Days 1 to 7 will be evaluated first (ie, Cohort 1). In the event that unacceptable toxicity occurs in Cohort 1, then oral azacitidine may be evaluated at lower dose levels (eg, 150 mg). If the dosing regimen is confirmed to be safe in Cohort 1, other cohorts will be evaluated sequentially. During the treatment phase, patients will be monitored closely for safety and tolerability. Dosing interruption or delay, dose or schedule reduction, intra-subject dose/schedule escalation or re-escalation may occur on the basis of protocol-specified dosing adjustment guidelines. Safety will be monitored throughout the study at predetermined intervals and as clinically indicated by vital signs, physical examination, performance status, laboratory tests and evaluation of adverse events. The patient can continue to receive the study treatment for up to 12 months provided that they benefit from the study treatment and all protocol-specified criteria are met. However, the patient may receive the study treatment for less than 12 months due to adverse event, disease recurrence or progression. When the study treatment is discontinued, all patients who have received at least one dose of oral azacitidine will be asked to see the study doctor for the treatment discontinuation visit. Thereafter, all patients discontinued from the study treatment will enter the Follow-up phase for safety and survival follow up.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| CC-486 | Experimental | Drug: CC-486Dose of 150 mg, 200 mg, or 300 mg once daily (QD) for the first 7, 10, or 14 days of each 28-day cycle, starting 42-84 days after transplantation. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (19 listed)
- Histologically confirmed Myelodysplastic Syndromes or Acute Myeloid Leukemia undergoing allogeneic hematopoietic stem cell transplantation with either peripheral blood or bone marrow as the source of hematopoietic stem cells
- No prior allogeneic HSCT; and
- No more than 1 antigen mismatch at Human Leukocyte Antigen (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%
Key exclusion criteria (12 listed)
- Use of any of the following after transplantation and prior to starting oral azacitidine:
- Active Graft-versus-host disease (GVHD) grade II or higher
- Any evidence of gastrointestinal (GI) GVHD
- Concurrent use of corticosteroids equivalent of prednisone at a dose > 0.5 mg/kg
- Known active viral infection with Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CC-486Also: Oral AzacitdineCohorts of 3 to 6 subjects will be treated at escalating or de-escalating sequential dose levels until a preliminary Maximum Tolerated Dose (MTD) is identified. | Drug | CC-486 |
Primary outcome
The Number of Participants With Dose Limiting Toxicities (DLT)
Time frame: 2 months (Cycles 1 and 2)
A DLT included events that started within 28 days of the first dose of CC-486 in a 28-day cycle, constituted a change from baseline irrespective of outcome, as decided by the investigator to be related to CC-486 including: * ≥ Grade (GR) 3 nausea, diarrhea, or vomiting despite the use of medical support * Other significant nonhematologic toxicity of ≥ GR 3 considered not related to the disease or intercurrent illness • Absolute neutrophil count (ANC) < 0.5 x 10^9/L for > 1 week despite growth factor support * Platelets < 25 x 10^9/L for > 1 week despite transfusion support * Failure of recovery to an ANC ≥ 1.0 x 10^9/L and/or platelets ≥ 50 x 10^9/L with a hypocellular marrow by 56 days after the start of a cycle of CC-486 not due to relapse or progressive disease. The maximum tolerated dose is defined as the cohort delivering the highest dose in which no more than 33% of the evaluable subjects had a DLT The safety population included subjects who received ≥ 1 dose of CC-486
Number of Participants With Treatment Emergent Adverse Events (TEAE)
Time frame: From the first dose of investigational product (IP) up to 28 days after the last dose of IP. The median duration of exposure was 252.5 days overall; up to the final data cut off date of 14 July 2017
A TEAE was defined as any AE with an onset date on or after the first dose of IP or any event already present that worsened in severity or increased in frequency after exposure to IP up to 28 days after the last dose. In addition, an AE that occurred beyond the timeframe and was assessed by the doctor as possibly related to IP was considered to be treatment-emergent. Severity was assessed using National Cancer Institute Common Toxicity Terminology Criteria for AEs (NCI CTCAE) version 4.0, where 1= Mild; 2= Moderate; 3= Severe; 4= Life-threatening; 5= Death related to AE. Serious AEs resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in a medical event that may have jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes above.
13 secondary outcomes
Percentage of Participants With Graft Versus Host Disease During the Entire Course of the Study
Time frame: From the first dose of CC-486 up to study discontinuation or death. Up to final data cut off date of 14 July 2017; up to 186 weeks and 4 days
Kaplan Meier Estimate of Time to Discontinuation From Treatment
Time frame: From the first dose of IP dose to the date of discontinuation from IP; the overall median time to discontinuation of IP was 283.5 days
Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration Of CC-486 (AUC-t)
Time frame: On Day 1, pharmacokinetic (PK) samples were collected at predose and over a 6-hour period following drug administration on the following schedule: 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours post-dose; Cycle 1 or 2 until 6 hours after CC-486 administration.
Area Under the Plasma Concentration-Time Curve From Time 0 to Extrapolated to Infinity (AUC-inf; AUC0-∞) Of CC-486
Time frame: On Day 1, PK samples were collected at predose and over the 6-hour period following CC-486 administration on the following schedule: 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours post-dose at Cycle 1 or 2 until 6 hours after CC-486 administration.
Maximum Observed Concentration (Cmax) Of CC-486
Time frame: On Day 1, PK samples were collected at predose and over the 6-hour period following CC-486 administration on the following schedule: 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours post-dose at Cycle 1 or 2 until 6 hours after CC-486 administration.
Time to Reach Maximum Concentration (Tmax) of CC-486
Time frame: On Day 1, PK samples were collected at predose and over the 6-hour period following CC-486 administration on the following schedule: 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours post-dose at Cycle 1 or 2 until 6 hours after CC-486 administration.
Terminal Half-Life (T1/2) of CC-486
Time frame: On Day 1, PK samples were collected at predose and over the 6-hour period following CC-486 administration on the following schedule: 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours post-dose at Cycle 1 or 2 until 6 hours after CC-486 administration.
Apparent Total Clearance (CL/F) of CC-486
Time frame: On Day 1, PK samples were collected at predose and over the 6-hour period following CC-486 administration on the following schedule: 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours post-dose at Cycle 1 or 2 until 6 hours after CC-486 administration.
Apparent Volume of Distribution (Vz/F) of CC-486
Time frame: On Day 1, PK samples were collected at predose and over the 6-hour period following CC-486 administration on the following schedule: 0.5, 1, 1.5, 2, 2.5, 3, 4, and 6 hours post-dose at Cycle 1 or 2 until 6 hours after CC-486 administration.
Percentage of Participants With Disease Relapse or Progression
Time frame: Date of first dose of IP to disease relapse or progression; up to data cut-off date of 14 July 2017; median number of days assessed was 963.0 days for Cohort 1, 743.5 days for Cohort 2, 675.5 days for Cohort 3A and 559.0 days for Cohort 3.
Time to Disease Recurrence/Progression
Time frame: Date of allogenic HSCT to disease progression or relaopse; up to data cut-off date of 14 July 2017; median number of days assessed was 963.0 days for Cohort 1, 743.5 days for Cohort 2, 675.5 days for Cohort 3A and 559.0 days for Cohort 3.
Overall Survival
Time frame: Date of the allogeneic HSCT to death from any cause. Median number of days participants were assessed from first dose to last contact was 963.0 days for Cohort 1, 743.5 days for Cohort 2, 675.5 days for Cohort 3A and 559.0 days for Cohort 3.
Kaplan Meier Estimate of Relapse-Free Survival (RFS)
Time frame: Date of allogenic HSCT to date of progression or death from any cause; Median number of days participants were assessed from first dose to last contact was 963 days for Cohort 1, 674.8 days for Cohort 2, 577.5 days for Cohort 3A and 553 days for Cohort 3
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Nov 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 29933073de Lima M, Oran B, Champlin RE, Papadopoulos EB, Giralt SA, Scott BL, William BM, Hetzer J, Laille E, Hubbell B, Skikne BS, Craddock C. CC-486 Maintenance after Stem Cell Transplantation in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndromes. Biol Blood Marrow Transplant. 2018 Oct;24(10):2017-2024. doi: 10.1016/j.bbmt.2018.06.016. Epub 2018 Jun 20.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Barry Skikne, M.D., FACP; FCP (SA) study director
Celgene Corporation
5 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing CC-486 in people with Leukemia, Myeloid, Acute and Myelodysplastic Syndromes, run by Celgene at 5 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 19 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Nov 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in United States, United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 Nov 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The Number of Participants With Dose Limiting Toxicities (DLT) (time frame: 2 months (Cycles 1 and 2)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01835587, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Nov 2018.