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

NCT02339740

Description:

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.

Related Conditions:
  • Acute Promyelocytic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Tretinoin and Arsenic Trioxide in Treating Patients With Untreated Acute Promyelocytic Leukemia
  • Official Title: A Phase III Study for Patients With Newly Diagnosed Acute Promyelocytic Leukemia (APL) Using Arsenic Trioxide and All-Trans Retinoic Acid

Clinical Trial IDs

  • ORG STUDY ID: AAML1331
  • SECONDARY ID: NCI-2014-02266
  • SECONDARY ID: AAML1331
  • SECONDARY ID: PAAML1331_A01PAMDREVW0
  • SECONDARY ID: AAML1331
  • SECONDARY ID: AAML1331
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT02339740

Conditions

  • Acute Promyelocytic Leukemia With PML-RARA

Interventions

DrugSynonymsArms
Arsenic TrioxideArsenic (III) Oxide, Arsenic Sesquioxide, Arsenous Acid, Arsenous Acid Anhydride, Arsenous Oxide, Trisenox, White ArsenicTreatment (tretinoin, arsenic trioxide, chemotherapy)
Cytarabine.beta.-Cytosine arabinoside, 1-.beta.-D-Arabinofuranosyl-4-amino-2(1H)pyrimidinone, 1-.beta.-D-Arabinofuranosylcytosine, 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-, 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, Cytosine Arabinoside, Cytosine-.beta.-arabinoside, Cytosine-beta-arabinoside, Erpalfa, Starasid, Tarabine PFS, U 19920, U-19920, Udicil, WR-28453Treatment (tretinoin, arsenic trioxide, chemotherapy)
DexamethasoneAacidexam, 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, VisumetazoneTreatment (tretinoin, arsenic trioxide, chemotherapy)
Idarubicin4-Demethoxydaunomycin, 4-demethoxydaunorubicin, 4-DMDRTreatment (tretinoin, arsenic trioxide, chemotherapy)
Mitoxantrone HydrochlorideCL 232315, DHAD, DHAQ, Dihydroxyanthracenedione Dihydrochloride, Mitoxantrone Dihydrochloride, Mitoxantroni Hydrochloridum, Mitozantrone Hydrochloride, Mitroxone, Neotalem, Novantrone, Onkotrone, PralifanTreatment (tretinoin, arsenic trioxide, chemotherapy)
Tretinoin2,4,6,8-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-, VitinoinTreatment (tretinoin, arsenic trioxide, chemotherapy)

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.

Detailed Description

      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 real-time
      (RT)-polymerase chain reaction (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 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (tretinoin, arsenic trioxide, chemotherapy)ExperimentalSee Detailed Description
  • Arsenic Trioxide
  • Cytarabine
  • Dexamethasone
  • Idarubicin
  • Mitoxantrone Hydrochloride
  • Tretinoin

Eligibility 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 excluded; 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
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:12 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event-free survival (EFS) in standard risk acute promyelocytic leukemia (APL) patients
Time Frame:Up to 24 months
Safety Issue:
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.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Children's Oncology Group

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