Tretinoin and Arsenic Trioxide in Treating Patients With Untreated Acute Promyelocytic Leukemia
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| ClinicalTrials.gov Identifier: NCT02339740 |
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Recruitment Status :
Active, not recruiting
First Posted : January 15, 2015
Results First Posted : December 16, 2021
Last Update Posted : May 23, 2023
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Sponsor:
Children's Oncology Group
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group
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Brief Summary:
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 or disease | Intervention/treatment | Phase |
|---|---|---|
| Acute Promyelocytic Leukemia With t(15;17)(q24.1;q21.2); PML-RARA | 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 | Phase 3 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 158 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (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 |
| Actual Study Start Date : | June 29, 2015 |
| Actual Primary Completion Date : | October 31, 2020 |
| Estimated Study Completion Date : | October 31, 2025 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Acute promyelocytic leukemia
| Arm | Intervention/treatment |
|---|---|
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Experimental: Treatment (tretinoin, arsenic trioxide, chemotherapy)
See Detailed Description
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Drug: Arsenic Trioxide
Given IV
Other Names:
Drug: Cytarabine Given IV
Other Names:
Drug: Dexamethasone Given PO or IV
Other Names:
Drug: Idarubicin Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Mitoxantrone Hydrochloride Given IV
Other Names:
Other: Quality-of-Life Assessment Ancillary studies
Other Name: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies Drug: Tretinoin Given PO
Other Names:
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Primary Outcome Measures :
- Event-free Survival (EFS) in Standard Risk Acute Promyelocytic Leukemia (APL) Patients [ Time Frame: Up to 24 months ]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.
- EFS in High Risk APL Patients [ Time Frame: Up to 24 months ]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.
Other Outcome Measures:
- 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 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.
- 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.
- 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 2 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 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 2 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 4 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 4 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 4 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 4 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 Psychosocial Functioning Over Time [ Time Frame: End of treatment to 4 years off-therapy ]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.
- Change in Parent-reported Quality of Life (QOL) Over Time [ Time Frame: End of treatment to 4 years ]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.
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| Ages Eligible for Study: | 12 Months to 21 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
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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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02339740
Locations
Show 174 study locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Matthew A Kutny | Children's Oncology Group |
Study Documents (Full-Text)
Documents provided by Children's Oncology Group:
Documents provided by Children's Oncology Group:
Study Protocol and Statistical Analysis Plan [PDF] March 16, 2018
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| 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 Posted: | January 15, 2015 Key Record Dates |
| Results First Posted: | December 16, 2021 |
| Last Update Posted: | May 23, 2023 |
| Last Verified: | May 2023 |
Additional relevant MeSH terms:
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Leukemia Leukemia, Promyelocytic, Acute Neoplasms by Histologic Type Neoplasms Leukemia, Myeloid, Acute Leukemia, Myeloid Vitamins Vitamin A Cytarabine Dexamethasone Dexamethasone acetate Mitoxantrone Idarubicin Tretinoin Retinol palmitate |
Arsenic Trioxide BB 1101 Micronutrients Physiological Effects of Drugs Anti-Inflammatory Agents Antiemetics Autonomic Agents Peripheral Nervous System Agents Gastrointestinal Agents Glucocorticoids Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Antineoplastic Agents, Hormonal Antineoplastic Agents Protease Inhibitors |