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Tretinoin and Arsenic Trioxide in Treating Patients With Untreated Acute Promyelocytic Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02339740
Recruitment Status : Active, not recruiting
First Posted : January 15, 2015
Results First Posted : December 16, 2021
Last Update Posted : May 23, 2023
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Acute Promyelocytic Leukemia With t(15;17)(q24.1;q21.2); PML-RARA
Interventions Drug: Arsenic Trioxide
Drug: Cytarabine
Drug: Dexamethasone
Drug: Idarubicin
Other: Laboratory Biomarker Analysis
Drug: Mitoxantrone Hydrochloride
Other: Quality-of-Life Assessment
Other: Questionnaire Administration
Drug: Tretinoin
Enrollment 158
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Standard Risk High Risk
Hide Arm/Group Description WBC <10,000 cells/µL WBC ≥10,000 cells/µL
Period Title: Overall Study
Started 101 57
Completed 92 53
Not Completed 9 4
Reason Not Completed
Death             1             0
Physician Decision             0             2
Withdrawal by Subject             5             1
Inevaluable-RQPCR positive not confirmed             3             1
Arm/Group Title Standard Risk High Risk Total
Hide Arm/Group Description WBC <10,000 cells/µL WBC ≥10,000 cells/µL Total of all reporting groups
Overall Number of Baseline Participants 101 57 158
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 101 participants 57 participants 158 participants
<=18 years
85
  84.2%
53
  93.0%
138
  87.3%
Between 18 and 65 years
16
  15.8%
4
   7.0%
20
  12.7%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 101 participants 57 participants 158 participants
13.9  (4.5) 12.3  (4.7) 13.4  (4.6)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 101 participants 57 participants 158 participants
Female
48
  47.5%
25
  43.9%
73
  46.2%
Male
53
  52.5%
32
  56.1%
85
  53.8%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 101 participants 57 participants 158 participants
Hispanic or Latino
32
  31.7%
14
  24.6%
46
  29.1%
Not Hispanic or Latino
56
  55.4%
37
  64.9%
93
  58.9%
Unknown or Not Reported
13
  12.9%
6
  10.5%
19
  12.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 101 participants 57 participants 158 participants
American Indian or Alaska Native
3
   3.0%
0
   0.0%
3
   1.9%
Asian
3
   3.0%
3
   5.3%
6
   3.8%
Native Hawaiian or Other Pacific Islander
1
   1.0%
0
   0.0%
1
   0.6%
Black or African American
13
  12.9%
13
  22.8%
26
  16.5%
White
60
  59.4%
34
  59.6%
94
  59.5%
More than one race
3
   3.0%
0
   0.0%
3
   1.9%
Unknown or Not Reported
18
  17.8%
7
  12.3%
25
  15.8%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 101 participants 57 participants 158 participants
United States 90 54 144
Canada 6 2 8
Australia 5 1 6
1.Primary Outcome
Title Event-free Survival (EFS) in Standard Risk Acute Promyelocytic Leukemia (APL) Patients
Hide Description EFS is defined as the time from on study to failure to achieve hematological complete response (CR) prior to start of consolidation, persistence of molecular positive disease after minimal residual disease (MRD) positive consolidation course, relapse (molecular, morphologic or extramedullary), or death. The Kaplan-Meier method will be used to estimate 2-year EFS along with 90% log-minus-log transformed confidence limits.
Time Frame Up to 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Patients ineligible, did not start treatment, or RQPCR positive not confirmed are excluded from analyses of EFS
Arm/Group Title Standard Risk
Hide Arm/Group Description:
WBC <10,000 cells/µL
Overall Number of Participants Analyzed 98
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: percentage of participants
97.9
(93.4 to 99.3)
2.Primary Outcome
Title EFS in High Risk APL Patients
Hide Description EFS is defined as the time from on study to failure to achieve hematological CR prior to start of consolidation, persistence of molecular positive disease after MRD positive consolidation course, relapse (molecular, morphologic or extramedullary), or death. The Kaplan-Meier method will be used to estimate 2-year EFS along with 90% log-minus-log transformed confidence limits.
Time Frame Up to 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
Patients ineligible, did not start treatment, or RQPCR positive not confirmed are excluded from analyses of EFS
Arm/Group Title High Risk
Hide Arm/Group Description:
WBC ≥10,000 cells/µL
Overall Number of Participants Analyzed 56
Measure Type: Number
Number (90% Confidence Interval)
Unit of Measure: percentage of participants
96.1
(88.2 to 98.8)
3.Other Pre-specified Outcome
Title Induction Death Rate for Patients With FLT3 Mutations and Wild Type FLT3
Hide Description A Fisher's exact test will be used to compare the induction death rate for patients with FLT3 mutations to patients with wild type FLT3.
Time Frame Up to 70 days
Outcome Measure Data Not Reported
4.Other Pre-specified Outcome
Title Disease Free Survival (DFS)
Hide Description For patients in remission at the end of induction, the log-rank test will be used to test for differences in DFS for those with end of induction real-time quantitative polymerase chain reaction (RQ-PCR) of < 1 normalized copy number (NCN) compared with those with end of Induction RQ-PCR >= 1 NCN.
Time Frame Up to 70 days
Outcome Measure Data Not Reported
5.Other Pre-specified Outcome
Title Incidence of Serious Early Coagulopathy Events, Defined as Grade 3 or Higher Hemorrhage or Thrombosis
Hide Description Will calculate the International Society of Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation (DIC) score and compare the sensitivity and specificity of ISTH with that of thrombomodulin using McNemar's test for paired data. To improve the predictive ability of the ISTH DIC score, will use a stepwise combination of biomarkers. Receiver operating characteristic (ROC) curve will be used to assess the accuracy in prediction of bleeding events during induction and the areas under the ROC curve will be compared.
Time Frame Up to 29 days of induction therapy
Outcome Measure Data Not Reported
6.Other Pre-specified Outcome
Title Change in CogState Scores, Defined as a Decline of 5 Units in Mean Scores Apparent at 2 Years Off Therapy
Hide Description Actual CogState scores for each domain at each time point will be summarized and examined by descriptive statistics and scatter plots. Change in score for a domain from end of induction will be calculated and summarized by descriptive statistics. The mean change of score from end of induction to a later time-point will be estimated with its 95% confidence interval. Linear mixed models using scores from all time-points as outcome will also be used to estimate the change in scores between time-points with adjustment for within-patient correlation of the score by random effects for individual patients.
Time Frame End of induction up to 2 years post-treatment
Outcome Measure Data Not Reported
7.Other Pre-specified Outcome
Title Change in Parent-reported Executive Functioning Over Time, Defined as a Decline of 5 Units in Mean Scores Apparent at 2 Years Off Therapy
Hide Description Measured by the Behavioral Regulation, Working Memory and Metacognition Indices of the Behavior Rating Inventory of Executive Function. Change in score for a domain from end of induction will be calculated and summarized by descriptive statistics. The mean change of score from end of induction to a later time-point will be estimated with its 95% confidence interval. Linear mixed models using scores from all time-points as outcome will be used to estimate change in scores between time-points with adjustment for within-patient correlation of the score by random effects for individual patients.
Time Frame End of induction up to 2 years post-treatment
Outcome Measure Data Not Reported
8.Other Pre-specified Outcome
Title Change in Intellectual Functioning, Defined by Declines on the Wechsler-derived Estimated Intelligence Quotient and Processing Speed Scores
Hide Description One sample t-test on the change of score will be used to examine if there is significant decline in neurocognitive function from end of induction to 2 years off therapy. Linear mixed models using scores from all time-points as outcome will also be used to estimate the change in scores between time-points with adjustment for within-patient correlation of the score by random effects for individual patients.
Time Frame End of treatment to 4 years post-treatment
Outcome Measure Data Not Reported
9.Other Pre-specified Outcome
Title Change in Memory Functioning, Defined by Declines on the Children's Memory Scale Faces and Stories Memory Scores
Hide Description One sample t-test on the change of score will be used to examine if there is significant decline in neurocognitive function from end of induction to 2 years off therapy. Linear mixed models using scores from all time-points as outcome will also be used to estimate the change in scores between time-points with adjustment for within-patient correlation of the score by random effects for individual patients.
Time Frame End of treatment to 4 years post-treatment
Outcome Measure Data Not Reported
10.Other Pre-specified Outcome
Title Change in Verbal Learning Functioning, Defined by Declines on the California Verbal Learning Test Total Score
Hide Description One sample t-test on the change of score will be used to examine if there is significant decline in neurocognitive function from end of induction to 2 years off therapy. Linear mixed models using scores from all time-points as outcome will also be used to estimate the change in scores between time-points with adjustment for within-patient correlation of the score by random effects for individual patients.
Time Frame End of treatment to 4 years post-treatment
Outcome Measure Data Not Reported
11.Other Pre-specified Outcome
Title Change in Adaptive Functioning, Defined by Declines on the Adaptive Behavior Assessment System-II General Adaptive Behavior Composite Score
Hide Description One sample t-test on the change of score will be used to examine if there is significant decline in neurocognitive function from end of induction to 2 years off therapy. Linear mixed models using scores from all time-points as outcome will also be used to estimate the change in scores between time-points with adjustment for within-patient correlation of the score by random effects for individual patients.
Time Frame End of treatment to 4 years post-treatment
Outcome Measure Data Not Reported
12.Other Pre-specified Outcome
Title Change in Parent-reported Psychosocial Functioning Over Time
Hide Description Psychosocial functioning over time as defined by declines on the Behavior Assessment System for Children-Second Edition (BASC-2) Anxiety, Depression, and Social Skills scores, and the Pediatric Quality of Life Inventory (PedsQL) Total and Physical Health scores.
Time Frame End of treatment to 4 years off-therapy
Outcome Measure Data Not Reported
13.Other Pre-specified Outcome
Title Change in Parent-reported Quality of Life (QOL) Over Time
Hide Description QOL over time as defined as declines on the BASC-2 Anxiety, Depression, and Social Skills scores, and the PedsQL Total and Physical Health scores.
Time Frame End of treatment to 4 years
Outcome Measure Data Not Reported
Time Frame While patients were on protocol therapy (including up to 6 courses) or during follow-up.
Adverse Event Reporting Description Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.
 
Arm/Group Title Standard Risk High Risk
Hide Arm/Group Description WBC <10,000 cells/µL WBC ≥10,000 cells/µL
All-Cause Mortality
Standard Risk High Risk
Affected / at Risk (%) Affected / at Risk (%)
Total   1/101 (0.99%)      0/57 (0.00%)    
Hide Serious Adverse Events
Standard Risk High Risk
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/101 (2.97%)      2/57 (3.51%)    
General disorders     
Death NOS †  1/101 (0.99%)  0/57 (0.00%)  0
Multi-organ failure †  1/101 (0.99%)  0/57 (0.00%)  0
Infections and infestations     
Infections and infestations - Other, specify †  1/101 (0.99%)  0/57 (0.00%)  0
Nervous system disorders     
Depressed level of consciousness †  1/101 (0.99%)  0/57 (0.00%)  0
Encephalopathy †  1/101 (0.99%)  0/57 (0.00%)  0
Intracranial hemorrhage †  1/101 (0.99%)  0/57 (0.00%)  0
Seizure †  1/101 (0.99%)  0/57 (0.00%)  0
Psychiatric disorders     
Psychosis †  0/101 (0.00%)  0 1/57 (1.75%) 
Respiratory, thoracic and mediastinal disorders     
Bronchopulmonary hemorrhage †  1/101 (0.99%)  0/57 (0.00%)  0
Respiratory failure †  1/101 (0.99%)  0/57 (0.00%)  0
Retinoic acid syndrome †  1/101 (0.99%)  1/57 (1.75%) 
Skin and subcutaneous tissue disorders     
Hypohidrosis †  1/101 (0.99%)  0/57 (0.00%) 
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Standard Risk High Risk
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   89/101 (88.12%)      50/57 (87.72%)    
Blood and lymphatic system disorders     
Anemia †  1/101 (0.99%)  0/57 (0.00%) 
Disseminated intravascular coagulation †  1/101 (0.99%)  2/57 (3.51%) 
Febrile neutropenia †  9/101 (8.91%)  3/57 (5.26%) 
Cardiac disorders     
Left ventricular systolic dysfunction †  0/101 (0.00%)  1/57 (1.75%) 
Sinus tachycardia †  0/101 (0.00%)  1/57 (1.75%) 
Ventricular arrhythmia †  4/101 (3.96%)  0/57 (0.00%) 
Ear and labyrinth disorders     
Hearing impaired †  1/101 (0.99%)  0/57 (0.00%) 
Tinnitus †  1/101 (0.99%)  0/57 (0.00%) 
Eye disorders     
Eye disorders - Other, specify †  1/101 (0.99%)  0/57 (0.00%) 
Papilledema †  3/101 (2.97%)  1/57 (1.75%) 
Periorbital edema †  1/101 (0.99%)  0/57 (0.00%) 
Vitreous hemorrhage †  2/101 (1.98%)  0/57 (0.00%) 
Gastrointestinal disorders     
Abdominal distension †  1/101 (0.99%)  0/57 (0.00%) 
Abdominal pain †  2/101 (1.98%)  2/57 (3.51%) 
Dental caries †  1/101 (0.99%)  0/57 (0.00%) 
Diarrhea †  0/101 (0.00%)  1/57 (1.75%) 
Dysphagia †  0/101 (0.00%)  1/57 (1.75%) 
Esophagitis †  0/101 (0.00%)  2/57 (3.51%) 
Mucositis oral †  0/101 (0.00%)  11/57 (19.30%) 
Nausea †  1/101 (0.99%)  1/57 (1.75%) 
Oral pain †  0/101 (0.00%)  1/57 (1.75%) 
Upper gastrointestinal hemorrhage †  0/101 (0.00%)  1/57 (1.75%) 
Vomiting †  3/101 (2.97%)  1/57 (1.75%) 
General disorders     
Fever †  2/101 (1.98%)  0/57 (0.00%) 
Non-cardiac chest pain †  1/101 (0.99%)  1/57 (1.75%) 
Pain †  2/101 (1.98%)  0/57 (0.00%) 
Hepatobiliary disorders     
Cholecystitis †  0/101 (0.00%)  1/57 (1.75%) 
Immune system disorders     
Anaphylaxis †  1/101 (0.99%)  1/57 (1.75%) 
Infections and infestations     
Bone infection †  0/101 (0.00%)  1/57 (1.75%) 
Catheter related infection †  3/101 (2.97%)  1/57 (1.75%) 
Enterocolitis infectious †  1/101 (0.99%)  0/57 (0.00%) 
Infections and infestations - Other, specify †  7/101 (6.93%)  5/57 (8.77%) 
Kidney infection †  1/101 (0.99%)  0/57 (0.00%) 
Lung infection †  2/101 (1.98%)  1/57 (1.75%) 
Mucosal infection †  0/101 (0.00%)  1/57 (1.75%) 
Paronychia †  1/101 (0.99%)  0/57 (0.00%) 
Sepsis †  0/101 (0.00%)  1/57 (1.75%) 
Skin infection †  0/101 (0.00%)  1/57 (1.75%) 
Urinary tract infection †  0/101 (0.00%)  1/57 (1.75%) 
Wound infection †  1/101 (0.99%)  0/57 (0.00%) 
Injury, poisoning and procedural complications     
Postoperative hemorrhage †  1/101 (0.99%)  0/57 (0.00%) 
Vascular access complication †  2/101 (1.98%)  0/57 (0.00%) 
Investigations     
Alanine aminotransferase increased †  16/101 (15.84%)  6/57 (10.53%) 
Aspartate aminotransferase increased †  11/101 (10.89%)  4/57 (7.02%) 
Blood bilirubin increased †  1/101 (0.99%)  1/57 (1.75%) 
Electrocardiogram QT corrected interval prolonged †  67/101 (66.34%)  43/57 (75.44%) 
Fibrinogen decreased †  1/101 (0.99%)  6/57 (10.53%) 
Investigations - Other, specify †  1/101 (0.99%)  1/57 (1.75%) 
Lipase increased †  1/101 (0.99%)  0/57 (0.00%) 
Weight gain †  0/101 (0.00%)  1/57 (1.75%) 
Metabolism and nutrition disorders     
Acidosis †  2/101 (1.98%)  0/57 (0.00%) 
Anorexia †  2/101 (1.98%)  0/57 (0.00%) 
Hypercalcemia †  1/101 (0.99%)  0/57 (0.00%) 
Hyperglycemia †  9/101 (8.91%)  7/57 (12.28%) 
Hyperkalemia †  1/101 (0.99%)  0/57 (0.00%) 
Hypernatremia †  0/101 (0.00%)  1/57 (1.75%) 
Hypertriglyceridemia †  1/101 (0.99%)  1/57 (1.75%) 
Hyperuricemia †  1/101 (0.99%)  0/57 (0.00%) 
Hypocalcemia †  1/101 (0.99%)  1/57 (1.75%) 
Hypokalemia †  5/101 (4.95%)  4/57 (7.02%) 
Hyponatremia †  0/101 (0.00%)  1/57 (1.75%) 
Hypophosphatemia †  1/101 (0.99%)  0/57 (0.00%) 
Musculoskeletal and connective tissue disorders     
Back pain †  1/101 (0.99%)  1/57 (1.75%) 
Myalgia †  1/101 (0.99%)  0/57 (0.00%) 
Neck pain †  1/101 (0.99%)  0/57 (0.00%) 
Pain in extremity †  2/101 (1.98%)  0/57 (0.00%) 
Nervous system disorders     
Cognitive disturbance †  1/101 (0.99%)  1/57 (1.75%) 
Depressed level of consciousness †  1/101 (0.99%)  0/57 (0.00%) 
Headache †  8/101 (7.92%)  4/57 (7.02%) 
Intracranial hemorrhage †  0/101 (0.00%)  3/57 (5.26%) 
Nervous system disorders - Other, specify †  1/101 (0.99%)  0/57 (0.00%) 
Neuralgia †  1/101 (0.99%)  0/57 (0.00%) 
Peripheral sensory neuropathy †  2/101 (1.98%)  0/57 (0.00%) 
Somnolence †  1/101 (0.99%)  0/57 (0.00%) 
Stroke †  0/101 (0.00%)  1/57 (1.75%) 
Psychiatric disorders     
Anxiety †  1/101 (0.99%)  1/57 (1.75%) 
Delirium †  0/101 (0.00%)  1/57 (1.75%) 
Irritability †  1/101 (0.99%)  0/57 (0.00%) 
Renal and urinary disorders     
Acute kidney injury †  3/101 (2.97%)  0/57 (0.00%) 
Hematuria †  1/101 (0.99%)  0/57 (0.00%) 
Renal calculi †  0/101 (0.00%)  1/57 (1.75%) 
Reproductive system and breast disorders     
Menorrhagia †  2/101 (1.98%)  1/57 (1.75%) 
Uterine hemorrhage †  1/101 (0.99%)  0/57 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Adult respiratory distress syndrome †  0/101 (0.00%)  1/57 (1.75%) 
Bronchopulmonary hemorrhage †  0/101 (0.00%)  1/57 (1.75%) 
Dyspnea †  2/101 (1.98%)  2/57 (3.51%) 
Epistaxis †  8/101 (7.92%)  2/57 (3.51%) 
Hypoxia †  5/101 (4.95%)  2/57 (3.51%) 
Laryngeal hemorrhage †  1/101 (0.99%)  0/57 (0.00%) 
Pleural effusion †  1/101 (0.99%)  1/57 (1.75%) 
Pneumonitis †  1/101 (0.99%)  0/57 (0.00%) 
Pulmonary edema †  3/101 (2.97%)  0/57 (0.00%) 
Respiratory failure †  0/101 (0.00%)  1/57 (1.75%) 
Respiratory, thoracic and mediastinal disorders - Other, specify †  1/101 (0.99%)  1/57 (1.75%) 
Retinoic acid syndrome †  3/101 (2.97%)  2/57 (3.51%) 
Sinus pain †  1/101 (0.99%)  0/57 (0.00%) 
Sore throat †  0/101 (0.00%)  1/57 (1.75%) 
Skin and subcutaneous tissue disorders     
Photosensitivity †  0/101 (0.00%)  1/57 (1.75%) 
Rash maculo-papular †  4/101 (3.96%)  2/57 (3.51%) 
Vascular disorders     
Hematoma †  1/101 (0.99%)  0/57 (0.00%) 
Hypertension †  1/101 (0.99%)  2/57 (3.51%) 
Hypotension †  4/101 (3.96%)  2/57 (3.51%) 
Thromboembolic event †  2/101 (1.98%)  1/57 (1.75%) 
†
Indicates events were collected by systematic assessment
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Must obtain prior approval.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Results Reporting Coordinator
Organization: Children's Oncology Group
Phone: 626-447-0064
EMail: resultsreportingcoordinator@childrensoncologygroup.org
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT02339740    
Other Study ID Numbers: AAML1331
NCI-2014-02266 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
PAAML1331_A01PAMDREVW0
AAML1331
AAML1331 ( Other Identifier: Children's Oncology Group )
AAML1331 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
First Submitted: January 13, 2015
First Posted: January 15, 2015
Results First Submitted: November 17, 2021
Results First Posted: December 16, 2021
Last Update Posted: May 23, 2023