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

This study is currently recruiting participants.
Verified July 2017 by Children's Oncology Group
Sponsor:
ClinicalTrials.gov Identifier:
NCT02339740
First Posted: January 15, 2015
Last Update Posted: July 19, 2017
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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group
January 13, 2015
January 15, 2015
July 19, 2017
June 2015
April 2023   (Final data collection date for primary outcome measure)
  • EFS in high risk (HR) APL patients [ Time Frame: 3 years ]
    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. Will be compared against a fixed EFS of 71.1% at 36 months, which was observed for patients with HR APL treated on AIDA 0493. The Kaplan-Meier method will be used to estimate 3 year EFS along with 90% log-minus-log transformed confidence limits.
  • Event-free survival (EFS) in standard risk (SR) APL patients [ Time Frame: 2 years ]
    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. EFS for patients with SR APL on will be compared against a fixed EFS of 91.3% at 24 months, which was observed for SR APL patients treated on AIDA 0493. The Kaplan-Meier method will be used to estimate 2 year EFS along with 90% log-minus-log transformed confidence limits.
  • Event-free survival (EFS) in standard risk (SR) APL patients [ Time Frame: 2 years ]
    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. EFS for patients with SR APL on will be compared against a fixed EFS of 91.3% at 24 months, which was observed for SR APL patients treated on AIDA 0493. The Kaplan-Meier method will be used to estimate 2 year EFS along with 90% log-minus-log transformed confidence limits.
  • EFS in high risk (HR) APL patients [ Time Frame: 3 years ]
    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. Will be compared against a fixed EFS of 71.1% at 36 months, which was observed for patients with HR APL treated on AIDA 0493. The Kaplan-Meier method will be used to estimate 3 year EFS along with 90% log-minus-log transformed confidence limits.
Complete list of historical versions of study NCT02339740 on ClinicalTrials.gov Archive Site
Not Provided
Not Provided
  • Change in adaptive functioning, defined by declines on the Adaptive Behavior Assessment System-II General Adaptive Behavior Composite score [ Time Frame: End of treatment to 2 years post-treatment ]
    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.
  • Change in CogState scores, defined as a decline of 5 units in mean scores apparent at 2 years off therapy [ Time Frame: End of induction up to 4 years post-treatment ]
    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 pat
  • Change in intellectual functioning, defined by declines on the Wechsler-derived estimated intelligence quotient and Processing Speed scores [ Time Frame: End of treatment to 2 years post-treatment ]
    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.
  • Change in memory functioning, defined by declines on the Children's Memory Scale Faces and Stories memory scores [ Time Frame: End of treatment to 2 years post-treatment ]
    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.
  • Change in parent-reported executive functioning over time, defined as a decline of 5 units in mean scores apparent at 2 years off therapy [ Time Frame: End of induction up to 4 years post-treatment ]
    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.
  • Change in verbal learning functioning, defined by declines on the California Verbal Learning Test Total score [ Time Frame: End of treatment to 2 years post-treatment ]
    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.
  • Disease free survival (DFS) [ Time Frame: Up to 70 days ]
    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 RQ-PCR of < 1 normalized copy number (NCN) compared with those with end of Induction RQ-PCR >= 1 NCN.
  • Incidence of serious early coagulopathy events, defined as grade 3 or higher hemorrhage or thrombosis [ Time Frame: Up to 29 days of induction therapy ]
    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.
  • Induction death rate for patients with FLT3 mutations and wild type FLT3 [ Time Frame: Up to 70 days ]
    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.
  • Induction death rate for patients with FLT3 mutations and wild type FLT3 [ Time Frame: Up to 70 days ]
    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.
  • Disease free survival (DFS) [ Time Frame: Up to 70 days ]
    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 RQ-PCR of < 1 normalized copy number (NCN) compared with those with end of Induction RQ-PCR >= 1 NCN.
  • Incidence of serious early coagulopathy events, defined as grade 3 or higher hemorrhage or thrombosis [ Time Frame: Up to 29 days of induction therapy ]
    Will calculate the International Society of Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation 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.
  • Change in CogState scores, defined as a decline of 5 units in mean scores apparent at 2 years off therapy [ Time Frame: End of induction up to 4 years post-treatment ]
    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 pat
  • Change in parent-reported executive functioning over time, defined as a decline of 5 units in mean scores apparent at 2 years off therapy [ Time Frame: End of induction up to 4 years post-treatment ]
    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.
  • Change in intellectual functioning, defined by declines on the Wechsler-derived estimated intelligence quotient and Processing Speed scores [ Time Frame: End of treatment to 2 years post-treatment ]
    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.
  • Change in memory functioning, defined by declines on the Children's Memory Scale Faces and Stories memory scores [ Time Frame: End of treatment to 2 years post-treatment ]
    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.
  • Change in verbal learning functioning, defined by declines on the California Verbal Learning Test Total score [ Time Frame: End of treatment to 2 years post-treatment ]
    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.
  • Change in adaptive functioning, defined by declines on the Adaptive Behavior Assessment System-II General Adaptive Behavior Composite score [ Time Frame: End of treatment to 2 years post-treatment ]
    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.
 
Tretinoin and Arsenic Trioxide in Treating Patients With Untreated Acute Promyelocytic Leukemia
A Phase III Study for Patients With Newly Diagnosed Acute Promyelocytic Leukemia (APL) Using Arsenic Trioxide and All-trans Retinoic Acid
This phase III trial studies tretinoin and arsenic trioxide in treating patients with newly diagnosed acute promyelocytic leukemia. Standard treatment for acute promyelocytic leukemia involves high doses of a common class of chemotherapy drugs called anthracyclines, which are known to cause long-term side effects, especially to the heart. Tretinoin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Arsenic trioxide may stop the growth of cancer cells by either killing the cells, by stopping them from dividing, or by stopping them from spreading. Completely removing or reducing the amount of anthracycline chemotherapy and giving tretinoin together with arsenic trioxide may be an effective treatment for acute promyelocytic leukemia and may reduce some of the long-term side effects.

PRIMARY OBJECTIVES:

I. To eliminate exposure to conventional chemotherapy (including anthracyclines), for patients with standard risk acute promyelocytic leukemia (APL), through use of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) (tretinoin) based therapy while achieving an event free survival (EFS) that is not inferior compared to historical controls.

II. To significantly reduce exposure to conventional chemotherapy, and in particular, anthracycline exposure, for patients with high risk APL, through use of ATO and ATRA based therapy while achieving an event free survival that is not inferior compared to historical controls.

SECONDARY OBJECTIVES:

I. To analyze the clinical impact of FMS-like tyrosine kinase 3 (FLT3) mutations in pediatric APL.

II. To correlate clinical outcomes with the kinetics of reduction in promyelocytic leukemia (PML)/retinoic acid receptor alpha (RARalpha) transcript level by quantitative reverse transcription-polymerase chain reaction (RT-PCR) (RQ-PCR) in bone marrow and peripheral blood samples from diagnosis to time points during therapy.

III. To monitor incidence of coagulopathy complications, utilizing standardized conventional supportive care, and correlate with a battery of coagulation testing.

IV. To evaluate the neurocognitive outcomes of patients treated on this protocol using patient-completed, performance-based measures of neuropsychological functioning and parent questionnaire report.

OUTLINE:

INDUCTION THERAPY: Patients with standard and high risk APL receive tretinoin orally (PO) twice daily (BID) and arsenic trioxide intravenously (IV) over 2-4 hours on days 1-28. High risk APL patients also receive dexamethasone PO or IV BID on days 1-14 and idarubicin hydrochloride IV over 15 minutes on days 1, 3, 5, and 7. Patients achieving hematologic complete remission (hCR)/hematologic complete remission with incomplete blood count recovery (hCRi) may go on to consolidation therapy. Patients who do not achieve hCR/hCRi may continue treatment with tretinoin and arsenic trioxide for up to 70 days.

CONSOLIDATION THERAPY: Patients receive tretinoin PO BID on days 1-14 and 29-42 and arsenic trioxide IV over 2-4 hours on days 1-5, 8-12, 15-19, and 22-26. Treatment repeats every 56 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive tretinoin PO BID on days 1-14 and arsenic trioxide IV over 2-4 hours on days 1-5, 8-12, 15-19, and 22-26.

MINIMAL RESIDUAL DISEASE (MRD) CONSOLIDATION THERAPY: Patients who have APL in the bone marrow after 2 courses of consolidation therapy receive MRD consolidation therapy prior to continuing onto consolidation course 3. Patients receive cytarabine IV over 1-3 hours every 12 hours on days 1-4; mitoxantrone hydrochloride IV over 15-30 minutes on days 3-6; and tretinoin PO BID on days 1-14. If there are no APL cells in the bone marrow after completion of MRD consolidation therapy, patients continue on to consolidation course 3.

After completion of study treatment, patients are followed up monthly for 12 months, every 3 months for 36 months, every 6 months for 48 months, and then annually for 2 years.

Interventional
Phase 3
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA
  • Childhood Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA
  • Untreated Adult Acute Myeloid Leukemia
  • Untreated Childhood Myeloid Neoplasm
  • Drug: Arsenic Trioxide
    Given IV
    Other Names:
    • Arsenic (III) Oxide
    • Arsenic Sesquioxide
    • Arsenous Acid
    • Arsenous Acid Anhydride
    • Arsenous Oxide
    • Trisenox
    • White Arsenic
  • Drug: Cytarabine
    Given IV
    Other Names:
    • .beta.-Cytosine arabinoside
    • 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone
    • 1-.beta.-D-Arabinofuranosylcytosine
    • 1.beta.-D-Arabinofuranosylcytosine
    • 2(1H)-Pyrimidinone, 4-amino-1.beta.-D-arabinofuranosyl-
    • Alexan
    • Ara-C
    • ARA-cell
    • Arabine
    • Arabinofuranosylcytosine
    • Arabinosylcytosine
    • Aracytidine
    • Aracytin
    • Aracytine
    • Beta-Cytosine Arabinoside
    • CHX-3311
    • Cytarabinum
    • Cytarbel
    • Cytosar
    • Cytosar-U
    • Cytosine Arabinoside
    • Cytosine-.beta.-arabinoside
    • Erpalfa
    • Starasid
    • Tarabine PFS
    • U 19920
    • U-19920
    • Udicil
    • WR-28453
  • Drug: Dexamethasone
    Given PO or IV
    Other Names:
    • Aacidexam
    • Adexone
    • Aknichthol Dexa
    • Alba-Dex
    • Alin
    • Alin Depot
    • Alin Oftalmico
    • Amplidermis
    • Anemul mono
    • Auricularum
    • Auxiloson
    • Baycuten
    • Baycuten N
    • Cortidexason
    • Cortisumman
    • Decacort
    • Decadrol
    • Decadron
    • Decalix
    • Decameth
    • Decasone R.p.
    • Dectancyl
    • Dekacort
    • Deltafluorene
    • Deronil
    • Desamethasone
    • Desameton
    • Dexa-Mamallet
    • Dexa-Rhinosan
    • Dexa-Scheroson
    • Dexa-sine
    • Dexacortal
    • Dexacortin
    • Dexafarma
    • Dexafluorene
    • Dexalocal
    • Dexamecortin
    • Dexameth
    • Dexamethasonum
    • Dexamonozon
    • Dexapos
    • Dexinoral
    • Dexone
    • Dinormon
    • Fluorodelta
    • Fortecortin
    • Gammacorten
    • Hexadecadrol
    • Hexadrol
    • Lokalison-F
    • Loverine
    • Methylfluorprednisolone
    • Millicorten
    • Mymethasone
    • Orgadrone
    • Spersadex
    • Visumetazone
  • Drug: Idarubicin
    Given IV
    Other Names:
    • 4-Demethoxydaunomycin
    • 4-Demethoxydaunorubicin
    • 4-DMDR
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Mitoxantrone Hydrochloride
    Given IV
    Other Names:
    • CL 232315
    • DHAD
    • DHAQ
    • Dihydroxyanthracenedione Dihydrochloride
    • Mitoxantrone Dihydrochloride
    • Mitoxantroni Hydrochloridum
    • Mitozantrone Hydrochloride
    • Mitroxone
    • Neotalem
    • Novantrone
    • Onkotrone
    • Pralifan
  • Other: Questionnaire Administration
    Ancillary studies
  • Drug: Tretinoin
    Given PO
    Other Names:
    • 2,4,6,8-Nonatetraenoic acid, 3, 7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-, (all-E)-
    • Aberel
    • Airol
    • Aknoten
    • all trans-Retinoic acid
    • All-trans Retinoic Acid
    • All-trans Vitamin A Acid
    • all-trans-Retinoic acid
    • all-trans-Vitamin A acid
    • ATRA
    • Avita
    • beta-Retinoic Acid
    • Cordes Vas
    • Dermairol
    • Epi-Aberel
    • Eudyna
    • Renova
    • Retin-A
    • Retin-A MICRO
    • Retin-A-Micro
    • Retinoic Acid
    • Retisol-A
    • Ro 5488
    • Stieva-A
    • Stieva-A Forte
    • Trans Retinoic Acid
    • Trans Vitamin A Acid
    • trans-Retinoic Acid
    • Tretinoinum
    • Vesanoid
    • Vitamin A Acid
    • Vitamin A acid, all-trans-
    • Vitinoin
Experimental: Treatment (tretinoin, arsenic trioxide, chemotherapy)
See Detailed Description
Interventions:
  • Drug: Arsenic Trioxide
  • Drug: Cytarabine
  • Drug: Dexamethasone
  • Drug: Idarubicin
  • Other: Laboratory Biomarker Analysis
  • Drug: Mitoxantrone Hydrochloride
  • Other: Questionnaire Administration
  • Drug: Tretinoin
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
158
April 2023
April 2023   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  • Patients must be newly diagnosed with a clinical diagnosis of APL (initially by morphology of bone marrow or peripheral blood)

    • Bone marrow is highly preferred but in cases where marrow cannot be obtained at diagnosis, peripheral blood will be accepted
  • If the RQ-PCR results are known at the time of study enrollment, the patient must demonstrate the PML-RARalpha transcript by RQ-PCR to be eligible
  • NOTE: A lumbar puncture is not required in order to be enrolled on study nor are lumbar punctures recommended at the time of diagnosis; if the diagnosis of APL is known or suspected, diagnostic lumbar punctures in patients with neurologic symptoms should be deferred until any coagulopathy is corrected; if central nervous system (CNS) disease is suspected or proven, a computed tomography (CT) or magnetic resonance imaging (MRI) should be considered to rule out the possibility of an associated chloroma; if CNS disease is documented, patients are still eligible and will receive protocol directed intrathecal treatments
  • Patients may receive up to a maximum of 5 days of pre-treatment with ATRA prior to administration of protocol therapy
  • Treatment with hydroxyurea, corticosteroids (any route) and intrathecal cytarabine prior to beginning protocol directed therapy is allowed; however, it should be noted that lumbar puncture and intrathecal therapy at initial diagnosis of APL is not recommended
  • All patients and/or their parents or legal guardians must sign a written informed consent
  • All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Exclusion Criteria:

  • Patients with secondary APL are excluded; this includes all patients with APL that may have resulted from prior treatment (chemotherapy or radiation)
  • Patients with isolated myeloid sarcoma (myeloblastoma, chloroma, including leukemia cutis) but without evidence of APL by bone marrow or peripheral blood morphology are excluded
  • Patients with a pre-existing diagnosis of a prolonged QT syndrome (even if corrected QT interval [QTc] is normal at the time of APL diagnosis) are excluded
  • Patients with a baseline QTc of > 450 msec are excluded; Bazett's formula is to be used for measurement of the corrected QT interval: the QT interval (msec) divided by the square root of the RR interval (msec)
  • Patients with a history or presence of significant ventricular or atrial tachyarrhythmia are excluded
  • Patients with right bundle branch block plus left anterior hemiblock, bifascicular block are excluded
  • Patients with serum creatinine > 3.0 mg/dL and patients on active dialysis for renal dysfunction are excluded
  • Patients who have received treatment with any other cytotoxic chemotherapy prior to beginning protocol therapy (other than allowed in above criteria) are excluded
  • Female patients who are pregnant are exclude; patients should not be pregnant or plan to become pregnant while on treatment; a pregnancy test prior to enrollment is required for female patients of childbearing potential
  • Lactating females who plan to breastfeed their infants are excluded
  • Sexually active patients of reproductive potential who have not agreed to be abstinent or use 2 forms of effective contraception during treatment through 1 month off therapy are excluded
Sexes Eligible for Study: All
1 Year to 21 Years   (Child, Adult)
No
United States
 
 
NCT02339740
AAML1331
NCI-2014-02266 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
AAML1331 ( Other Identifier: Children's Oncology Group )
AAML1331 ( Other Identifier: CTEP )
U10CA180886 ( U.S. NIH Grant/Contract )
Yes
Not Provided
Not Provided
Children's Oncology Group
Children's Oncology Group
National Cancer Institute (NCI)
Principal Investigator: Matthew Kutny Children's Oncology Group
Children's Oncology Group
July 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP