Clinical Trial Results:
A randomized, multicenter, open-label, Phase 2 study with a safety run-in part to evaluate safety, pharmacodynamics and efficacy of azacitidine compared to no anticancer treatment in children and young adults with acute myeloid leukemia in molecular relapse after first complete remission
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Summary
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EudraCT number |
2014-002172-92 |
Trial protocol |
DE DK NL FR |
Global end of trial date |
08 Oct 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
17 Apr 2020
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First version publication date |
17 Apr 2020
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
AZA-AML-004
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02450877 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Celgene Corporation
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Sponsor organisation address |
86 Morris Avenue, Summit, United States, 07901
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Public contact |
Clinical Trial Disclosure, Celgene Corporation, 01 908-673-9100, ClinicalTrialDisclosure@Celgene.com
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Scientific contact |
Bouchra Benettaib, Celgene Corporation, 01 908 673 9194, BBenettaib@Celgene.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
01 Nov 2019
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
08 Oct 2019
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
Safety Run-in Part
To establish a safe and tolerable dose of azacitidine to be used in the randomized part of the study.
Randomized Part
To evaluate the effect of azacitidine treatment in acute myeloid leukemia (AML) subjects at molecular relapse after complete response (CR1) when compared to no treatment with regard to the progression-free rate (PFR) at Day 84 (±4 days) post randomization.
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Protection of trial subjects |
Patient Confidentiality, Informed Consent, Archiving of Essential Documents,
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
12 Aug 2015
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety, Efficacy | ||
Long term follow-up duration |
1 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Denmark: 4
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Country: Number of subjects enrolled |
Germany: 1
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Country: Number of subjects enrolled |
Netherlands: 2
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Worldwide total number of subjects |
7
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EEA total number of subjects |
7
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
6
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Adolescents (12-17 years) |
1
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Seven children were enrolled from 3 centers located in Denmark, Germany and the Netherlands. | ||||||||||||
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Pre-assignment
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Screening details |
The Randomized Part of the study was not conducted. The study was transitioned to a single-arm study (N=20) Phase 2 non-Celgene sponsored study. | ||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||
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Arms
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Arm title
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Azacitidine | ||||||||||||
Arm description |
Participants received azacitidine 100 mg/m^2 by intravenous administration on days 1 to 7 of each 28-day treatment cycle for a maximum of 3 cycles. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Azacitidine
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Investigational medicinal product code |
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Other name |
Vidaza
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Azacitidine 100 mg/m^2 by IV administration on days 1 to 7 of each 28 day treatment cycle.
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Baseline characteristics reporting groups
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Reporting group title |
Azacitidine
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Reporting group description |
Participants received azacitidine 100 mg/m^2 by intravenous administration on days 1 to 7 of each 28-day treatment cycle for a maximum of 3 cycles. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Azacitidine
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Reporting group description |
Participants received azacitidine 100 mg/m^2 by intravenous administration on days 1 to 7 of each 28-day treatment cycle for a maximum of 3 cycles. | ||
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End point title |
Part 1 Safety Run In: Number of Participants with Dose Limiting Toxicities (DLT) [1] | ||||||
End point description |
Dose limiting toxicities were evaluated during the Part 1 Safety Run-in period in the first 6 subjects during Cycle 1. The severity grading was determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.03. A DLT is defined as below:
Hematologic DLT:
• Grade 3 or 4 hematologic toxicity requiring treatment delay > 21 days
(disease-related Grade 3 or 4 hematologic toxicity was not counted as a DLT)
Non-Hematologic DLT:
• Grade 4 nonhematologic toxicity (excluding transient transaminase elevation)
• Grade 3 nonhematological toxicity lasting more than 7 days despite optimal treatment
with standard supportive measures
• Grade 5 Adverse Events (AEs) considered related to study treatment
The safety population was defined as all subjects who received at least 1 dose of study therapy if assigned to receive azacitidine.
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End point type |
Primary
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End point timeframe |
Cycle 1 (28 days)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was performed. |
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| No statistical analyses for this end point | |||||||
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End point title |
Number of Participants with Treatment Emergent Adverse Events (TEAE) [2] | ||||||||||||||||||||||||||
End point description |
Treatment emergent adverse events were defined as any AEs occurring or worsening on or after the first treatment of the study medication and up to and including 28 days after the last dose. The intensity of AEs was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) (version 4.0, May 2009). For all other AEs not described in the NCI-CTCAE criteria, the intensity was assessed by the investigator as mild (grade 1), moderate (grade 2), severe (grade 3), life-threatening (grade 4) or death (grade 5). The safety population was defined as all subjects who received at least 1 dose of study therapy if assigned to receive azacitidine.
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End point type |
Primary
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End point timeframe |
From the first dose of investigational product (IP) up to and including 28 day after the last dose of azacitidine; up to 01 November 2019; median treatment duration was 12.00 weeks, with minimum and maximum durations of 8.0 and 13.9 weeks, respectively.
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was performed. |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||
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End point title |
Number of Participants with a Molecular Response [by Minimal Residual Disease (MRD)] at Day 84 | ||||||
End point description |
The number of participants with a molecular response was defined as the number of subjects with molecular response [1 log or more decrease in defined MRD molecular markers from baseline for all subject-specific genes or aberrations in peripheral blood (PB) samples and bone marrow (BM) aspirates]. The ITT population included participants who were enrolled in the study regardless of whether or not they received any of the study treatment.
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End point type |
Secondary
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End point timeframe |
Date of Enrollment to Day 84
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| No statistical analyses for this end point | |||||||
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End point title |
Maximum Plasma Concentration (Cmax) of Azacitidine | ||||||||
End point description |
Cmax was defined as the observed maximum plasma concentration, obtained directly from the observed concentration versus time. The pharmacokinetic (PK) population consisted of all subjects who had sufficient concentration-time data to enable the calculation of PK parameters for azacitidine.
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End point type |
Secondary
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End point timeframe |
Subjects ≤20 kg, pre-dosing at Cycle 1 Day 5 and 6 (C1 D5,D6) and post dose at Cycle 1 Day 7 (C1D7) at 5 min, 0.5 hours, 1, 4, and 6 hours; subjects > 20 kg, pre-dosing at C1 D5,D6 and D7, post dose on C1D7 at 5 min, 0.5 hours, 1, 2, 4, 6 hours.
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| No statistical analyses for this end point | |||||||||
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End point title |
Time to Maximum Plasma Concentration (Tmax) of Azacitidine | ||||||||
End point description |
Tmax was defined as the observed time to maximum plasma concentration of azacitidine. The pharmacokinetic population consisted of all subjects who had sufficient concentration-time data to enable the calculation of PK parameters for azacitidine.
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End point type |
Secondary
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End point timeframe |
Subjects ≤20 kg, pre-dosing at C1 D5, D6 and post dose at C1 D7 at 5 min, 0.5 hours, 1, 4, and 6 hours; subjects > 20 kg, pre-dosing at C1 D5, D6 and D7, post dose on C1 D7 at 5 min, 0.5 hours, 1, 2, 4, 6 hours.
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Plasma Concentration Versus Time Curve from Time 0 to the Last Quantifiable Concentration (AUC0-t) of Azacitidine | ||||||||
End point description |
AUC0-t was defined as the area under the plasma concentration-time curve from time zero to the last quantifiable time point, for azacitidine, calculated by the linear trapezoidal rule. The pharmacokinetic population consisted of all subjects who had sufficient concentration-time data to enable the calculation of PK parameters for azacitidine.
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End point type |
Secondary
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End point timeframe |
Subjects ≤20 kg, pre-dosing at C1 D5, D6 and post dose at C1 D7 at 5 min, 0.5 hours, 1, 4, and 6 hours; subjects > 20 kg, pre-dosing at C1 D5, D6 and D7, post dose on C1 D7 at 5 min, 0.5 hours, 1, 2, 4, 6 hours.
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Plasma Concentration-time Curve from Time 0 to 24 Hours Post-dose (AUC0-24) of Azacitidine | ||||||||
End point description |
Area under the plasma concentration-time curve from time 0 to 24 hours post- dose of azacitidine following multiple doses of azacitidine. The pharmacokinetic population consisted of all subjects who had sufficient concentration-time data to enable the calculation of PK parameters for azacitidine.
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End point type |
Secondary
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End point timeframe |
Subjects ≤20 kg, pre-dosing at C1 D5, D6 and post dose at C1 D7 at 5 min, 0.5 hours, 1, 4, and 6 hours; subjects > 20 kg, pre-dosing at C1 D5, D6 and D7, post dose on C1 D7 at 5 min, 0.5 hours, 1, 2, 4, 6 hours.
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Plasma Concentration-time Curve from Time Zero 0 Infinity (AUC∞) of Azacitidine | ||||||||
End point description |
Area under the plasma concentration-time curve from time zero to infinity, extrapolated to infinity, calculated by the linear trapezoidal rule and extrapolated to infinity and was calculated according to the following equation: AUC∞ = AUCt + (Ct/λz), where Ct is the last quantifiable concentration. No AUC extrapolation was performed with unreliable λz. If AUC% Ext was > 25%, AUC∞ was not be reported. The pharmacokinetic population consisted of all subjects who had sufficient concentration-time data to enable the calculation of PK parameters for azacitidine.
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End point type |
Secondary
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End point timeframe |
Subjects ≤20 kg, pre-dosing at C1 D5, D6 and post dose at C1 D7 at 5 min, 0.5 hours, 1, 4, and 6 hou
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| No statistical analyses for this end point | |||||||||
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End point title |
Terminal Phase Rate Constant (λz) of Azacitdine | ||||||||
End point description |
Terminal phase rate constant, determined by linear regression of the terminal points of the log-linear plasma concentration-time curve. The pharmacokinetic population consisted of all subjects who had sufficient concentration-time data to enable the calculation of PK parameters for azacitidine.
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End point type |
Secondary
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End point timeframe |
Subjects ≤20 kg, pre-dosing at C1 D5, D6 and post dose at C1 D7 at 5 min, 0.5 hours, 1, 4, and 6 hours; subjects > 20 kg, pre-dosing at C1 D5, D6 and D7, post dose on C1 D7 at 5 min, 0.5 hours, 1, 2, 4, 6 hours.
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| No statistical analyses for this end point | |||||||||
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End point title |
Terminal Phase Half-life (t½) of Azacitidine | ||||||||
End point description |
Terminal phase half-life was calculated according to the following equation: t½ = 0.693/λz. The pharmacokinetic population consisted of all subjects who had sufficient concentration-time data to enable the calculation of PK parameters for azacitidine.
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End point type |
Secondary
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End point timeframe |
Subjects ≤20 kg, pre-dosing at C1 D5, D6 and post dose at C1 D7 at 5 min, 0.5 hours, 1, 4, and 6 hours; subjects > 20 kg, pre-dosing at C1 D5, D6 and D7, post dose on C1 D7 at 5 min, 0.5 hours, 1, 2, 4, 6 hours.
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| No statistical analyses for this end point | |||||||||
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End point title |
Apparent Total Plasma Clearance (CL/) of Azacitidine | ||||||||
End point description |
Apparent total clearance was calculated as Dose/AUC∞. The pharmacokinetic population consisted of all subjects who had sufficient concentration-time data to enable the calculation of PK parameters for azacitidine.
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End point type |
Secondary
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End point timeframe |
Subjects ≤20 kg, pre-dosing at C1 D5, D6 and post dose at C1 D7 at 5 min, 0.5 hours, 1, 4, and 6 hours; subjects > 20 kg, pre-dosing at C1 D5, D6 and D7, post dose on C1 D7 at 5 min, 0.5 hours, 1, 2, 4, 6 hours.
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| No statistical analyses for this end point | |||||||||
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End point title |
Apparent Volume of Distribution (Vz/F) of Azacitidine | ||||||||
End point description |
Apparent volume of distribution of azacitidine was calculated according to the equation Vz = (CL)/λz. The pharmacokinetic population consisted of all subjects who had sufficient concentration-time data to enable the calculation of PK parameters for azacitidine.
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End point type |
Secondary
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End point timeframe |
Subjects ≤20 kg, pre-dosing at C1 D5, D6 and post dose at C1 D7 at 5 min, 0.5 hours, 1, 4, and 6 hours; subjects > 20 kg, pre-dosing at C1 D5, D6 and D7, post dose on C1 D7 at 5 min, 0.5 hours, 1, 2, 4, 6 hours.
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| No statistical analyses for this end point | |||||||||
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End point title |
Kaplan Meier Estimate of Leukemia-free Survival (LFS) | ||||||||
End point description |
Leukemia-free survival was defined as the time from study enrollment until disease progression (identified as clinical progression/clinical relapse) or death. Subjects alive and disease progression free at the time of the statistical analysis were censored at the time they were last known to be alive. The Intent to Treat population included participants who were enrolled in the study regardless of whether or not they received any of the study treatment.
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End point type |
Secondary
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End point timeframe |
From the time of study enrollment until the end of the safety run-in period; median follow-up time was 14.5 months (14.0 months to 36.0 months)
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| Notes [3] - 99999 = Median not calculable; more than 50% of subjects had not had a LFS event at time of analysis |
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| No statistical analyses for this end point | |||||||||
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End point title |
Minimal Residual Disease Level (MRD) at Day 84 | ||||||||
End point description |
Minimal residual disease was analyzed using real-time polymerase chain reaction (RQ-PCR) of a subject specific fusion gene or aberration. MRD level was used to evaluate response based on following guideline:
- Molecular stabilization was defined as < 1 log decrease or increase of specific PCR marker from baseline.
- Molecular progression was defined as ≥ 1 log increase of specific PCR marker from baseline to a level of 5 x 10^-4 or above in the absence of signs of clinical relapse, in MRD-negative subjects. The rise had to be at least 1 log (10-fold) greater than previous sensitivity to a level of 5 x 10^-4 or above.
- Molecular improvement was defined as ≥ 1 log decrease of specific PCR marker from baseline.
- Clinical relapse was defined as at least 5% blasts in peripheral blood (PB) and/or BM and/or proven histological extramedullary relapse.
The population included are the subjects with Day 84 information and completed treatment period
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End point type |
Secondary
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End point timeframe |
Enrollment to Day 84
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| Notes [4] - Levels in bone marrow are for 4 subjects at day 84 |
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| No statistical analyses for this end point | |||||||||
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End point title |
Kaplan-Meier Estimate of Overall Survival | ||||||||
End point description |
Overall survival was defined as the time from study enrollment (safety run-in part) until death from any cause. Subjects alive at the time of the statistical analysis were censored at the time they were last known to be alive. The ITT population included participants who were enrolled in the study regardless of whether or not they received any of the study treatment.
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End point type |
Secondary
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End point timeframe |
From the time of study enrollment until the end of the safety run-in period; up to 09 October 2019; median follow-up time was 14.5 months (range: 14.0 months to 36.0 months)
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| Notes [5] - 99999 = median overall survival not reached due to low number of events. |
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From the date of the first dose of study drug up to and including 28 days after the last dose of study drug. Median treatment duration was 12.00 weeks, with minimum and maximum duration of 8.0 and 13.9 weeks, respectively.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.0
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Reporting groups
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Reporting group title |
Azacitidine 100mg/m^2
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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16 Jan 2015 |
• To address Germany’s Federal Institute of Drugs and Medical Devices (BfArM) concerns regarding blood volumes, this amendment reduced the amount of blood being collected for PK. Each collection timepoint now required 1 mL of blood instead of 2 mL of blood. Also, for pediatric subjects weighing ≤ 20 kg, in order to minimize blood collection for these smaller children, only 5 timepoints were collected for PK assessments on Cycle 1 Day 7 (5 minutes postdose, 30 minutes postdose, 1 hour postdose, 4 hours postdose and 6 hours postdose), as opposed to the 7 collection timepoints required for subjects weighing > 20 kg (prior to dosing, 5 minutes postdose, 30 minutes postdose, 1 hour postdose, 2 hours postdose, 4 hours postdose and 6 hours postdose).
• To address BfArM’s concerns regarding dose reductions due to renal impairment and to be consistent with the azacitidine investigator’s brochure, dose reduction guidelines based on fluctuations in serum creatinine were added to the protocol. The statement that dose adjustments were not allowed was removed.
• In order to further minimize blood collection for this pediatric population, the blood volumes for hematology assessments were reduced from 2 mL to 1 mL at each timepoint.
• The detailed guidance to destroy/return used or unused azacitidine vials was replaced with protocol template language that the clinical research associate was to review with the site the process for return/disposal/destruction of the IV vials. |
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14 May 2015 |
Clarification: the collection of the samples for confirmation of MR was to occur within 7 days of the detection of MR.
Clarification: confirmation of MR required PB and BM MRD levels to be higher than the MRD level in the PB at the time of detection.
Clarification: point of entry of subjects into the Long-term Follow-up Period (LTFUP) after 28 day safety follow-up was clarified for the Safety Run-in Part (SRI) and for the Randomized Part (RP)..
Clarification: if HSCT was performed during the LTFU, a clinic visit had to occur pre-HSCT and at 3 and 6 months post-HSCT to have BM samples collected.
Inclusion criteria regarding first CR1 for both SRI Part and RP were revised.
For the RP, the collection of SAEs related to HSCT was added to the LTFU Period.
Clarification: specific predrug eligibility criteria had to be verified prior to randomizing the subject into the RP.
A 14-day visit window was added to Day 1 of Cycles 2 and 3 in the SRI Part and the EA of the RP.
Clarification: the LTFU Period would last for 2 years from last subject enrolled/randomized.
Guidances added for pregnancy testing for females ≥8 years or achieved menarche and for subjects <18 who reached the age of 18 while being treated that they had to agree to undergo physician approved reproductive education and discuss the side effects of study therapy with study doctor.
Clarification: archived BM aspirate from initial diagnosis needed to be sent to the central laboratory in the RP only.
Windows for PK blood sampling timepoints were added
Clarification: in the Randomized Part, the central laboratory would use the BM aspirate sample from initial diagnosis to confirm the molecular aberrations
Clarification: added about the IV solution preparation and administration time.
Clarification: added about the treatment delay exception in start of 2nd and 3rd cycles due to renal toxicity
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26 Oct 2017 |
• Molecular response (MR) at Day 84 (± 4 days) (or end of Cycle 3, if not the same date) was included as a secondary efficacy endpoint for the Safety Run-in Part. MR at end of Cycle 3 or Day 84 (± 4 days) (or end of Cycle 3, if not the same date) was added to evaluate the preliminary efficacy of the IP in the Safety Run-in Part prior to start of the Randomized Portion and to minimize subject exposure if the IP was not efficacious.
• The secondary endpoints of changes in DNA methylation (assessments of BM samples using Nano-HELP assay) and MRD at 3 and 6 months post-HSCT were deleted in the Safety Run-in Part . A decision was made to evaluate these in the Randomized Phase only since sufficient patient information would be available for informative analysis. Deletion of these endpoints in a Safety Run-in would minimize unnecessary assessment and subject burden, especially in regard to frequent BM biopsies that are not standard of care.
• Sample size of the Safety Run-in Part was increased from 12 to 18 to allow 6 additional subjects to enroll to assess preliminary efficacy prior to start of the Randomized Portion and to minimize subject exposure if the IP was not efficacious. 6 subjects had already been enrolled to the 100 mg/m2 dose of AZA. If this dose was deemed not safe or tolerable, 6 additional subjects were to be enrolled in a 75 mg/m2 cohort. Once the safe and tolerable dose level was determined, 6 further subjects were to be treated at the highest tolerated dose to gain preliminary efficacy, for a potential sample size of 18 patients (6 subjects in 100 mg/m2 cohort, 6 subjects in the 75 mg/m2 cohort, 6 subjects to assess preliminary efficacy).
The Long-term Follow-up was reduced to 1 year from the last dose of IP instead of 2 years from last subject enrolled since there were no safety concerns and 1 year of information post last dose would provide enough safety information and should allow sufficient time to follow the subjects through HSCT.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| The Randomized Part of the study was not conducted. The study was transitioned to a single-arm study (N=20) Phase 2 non-Celgene sponsored study. | |||
