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

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2016 by Children's Oncology Group
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group
ClinicalTrials.gov Identifier:
NCT02339740
First received: January 13, 2015
Last updated: July 8, 2016
Last verified: July 2016
  Purpose
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.

Condition Intervention Phase
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
Drug: Cytarabine
Drug: Dexamethasone
Drug: Idarubicin
Other: Laboratory Biomarker Analysis
Drug: Mitoxantrone Hydrochloride
Other: Questionnaire Administration
Drug: Tretinoin
Phase 3

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase III Study for Patients With Newly Diagnosed Acute Promyelocytic Leukemia (APL) Using Arsenic Trioxide and All-trans Retinoic Acid

Resource links provided by NLM:


Further study details as provided by Children's Oncology Group:

Primary Outcome Measures:
  • 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.


Other Outcome Measures:
  • 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.


Estimated Enrollment: 158
Study Start Date: June 2015
Estimated Primary Completion Date: April 2023 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (tretinoin, arsenic trioxide, chemotherapy)
See Detailed Description
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

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   1 Year to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02339740

Locations
United States, Pennsylvania
Children's Oncology Group Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Matthew A. Kutny    205-638-9285    mkutny@peds.uab.edu   
Principal Investigator: Matthew A. Kutny         
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
Principal Investigator: Matthew Kutny Children's Oncology Group
  More Information

Responsible Party: Children's Oncology Group
ClinicalTrials.gov Identifier: NCT02339740     History of Changes
Other Study ID Numbers: AAML1331
NCI-2014-02266 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
AAML1331 ( Other Identifier: Children's Oncology Group )
AAML1331 ( Other Identifier: CTEP )
U10CA180886 ( US NIH Grant/Contract Award Number )
Study First Received: January 13, 2015
Last Updated: July 8, 2016

Additional relevant MeSH terms:
Leukemia, Myeloid, Acute
Leukemia
Leukemia, Promyelocytic, Acute
Leukemia, Myeloid
Neoplasms by Histologic Type
Neoplasms
Dexamethasone acetate
Dexamethasone
Dexamethasone 21-phosphate
Arsenic trioxide
Retinol palmitate
Cytarabine
Tretinoin
Idarubicin
Mitoxantrone
Vitamins
Vitamin A
BB 1101
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Micronutrients

ClinicalTrials.gov processed this record on March 23, 2017